Category Archives: Epigenetics

In the spring of 2006 I gave a talk on the campus of Cornell University and afterwards was joined by then Cornell professors Richard Harrison and Kern Reeve for a sort of panel discussion or debate about biological evidences and origins. I presented a dozen or so interesting and important evidences that I felt needed to be recognized in any discussion of origins. The evidences falsified key predictions of evolution and so needed to be acknowledged and reckoned with, one way or another.

One of the items on my list was the so-called directed adaptation mechanisms which, broadly construed, can include everything from non-random, directed, mutations to transgenerational epigenetic inheritance. But I was in for a big surprise when Harrison and Reeve gave their response.

Directed adaptation is reminiscent of Lamarckism. Rather than natural selection acting over long time periods on biological variation which is random with respect to need, directed adaptation mechanisms provide rapid biological change in response to environmental challenges. Like physiological responses, directed adaptation can help an organism adjust to shifts in the environment. But those adaptations can then be inherited by later generations. Stresses which your grandparents were subjected to may be playing out in your own cells.

In the 20th century, evolutionists had strongly rejected any such capability. Lamarckism was the third rail in evolutionary circles. And for good reason, for it would falsify evolutionary theory. But empirical evidence had long since pointed toward the unthinkable, and by the 21st century the evidence was rapidly mounting.

While there was of course still much to learn in 2006 about directed adaptation (as there still is today for that matter), it could no longer be denied, and needed to be addressed. At least, that is what I thought.

I was shocked when Harrison and Reeve flatly denied the whole story. Rick waved it off as nothing more than some overblown and essentially discredited work done by Barry Hall and John Cairns, back in the 1970s and 80s (for example here).

But there was a body of work that had gone far beyond the work of Hall and Cairns. Incredulously I responded that entire books had been written on the subject. Rick was quick to respond that entire books are written about all kinds of discredited things.

True enough. It was me versus two professors on their home turf with a sympathetic audience, and there was no way that I was going to disabuse them of what they were convinced of.

Confirmation testing and theory-laden evidence are not merely philosophical notions. They are very real problems. Im reminded of all this every time a new study adds yet more confirmation to the directed adaptation story, such as the recent paper out of Nicola Iovinos lab on transgenerational epigenetic inheritance in house flies, which states:

Gametes carry parental genetic material to the next generation. Stress-induced epigenetic changes in the germ line can be inherited and can have a profound impact on offspring development.

The press release gives little indication of the controversy as it admits that these findings were once considered impossible:

It has long been thought that these epigenetic modifications never cross the border of generations. Scientists assumed that epigenetic memory accumulated throughout life is entirely cleared during the development of sperms and egg cells.

It is hard enough to see how organisms can respond intra-lifetime to environmental challenges, but how can it be inherited as well? For epigenetic changes that occur in somatic cells, that information must enter into the germ line as well. Somehow it must be incorporated into the sperm and/or egg cells.

It is an enormous problem to explain how such capabilities evolved. Not only are a large number of mutations required to make this capability work, it would not be selected for until the particular environmental condition occurred. That means that, under evolution, it would be not preserved, even if it could somehow arise by chance.

Photo credit: Epigenetic inheritance in fruit flies (more information here),by MPI of Immunobiology a. Epigenetics/ F. Zenk, via Science Daily.

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Evolution's Third Rail Transgenerational Epigenetics Can Have a Profound Impact - Discovery Institute

July 30, 2013 WhatIsEpigenetics Educationally Entertaining

In simplified terms, epigenetics is the study of biological mechanisms that will switch genes on and off. What does that mean? Well, if you are new to this whole thing, we first need a quick crash course in biochemistry and genetics:

Now that you understand genetics, lets learn about epigenetics. Epigenetics, essentially, affects how genes are read by cells, and subsequently how they produce proteins. Here are a few important points about epigenetics:

SEE ALSO: Could Stressed Fathers Epigenetically Give their Children High Blood Sugar?

Heres an analogy that might further help you to understand epigenetics. Think of the human life span as a very long movie. The cells would be the actors and actresses, essential units that make up the movie. DNA, in turn, would be the script instructions for all the participants of the movie to perform their roles. Subsequently, the DNA sequence would be the words on the script, and certain blocks of these words that instruct key actions or events to take place would be the genes. The concept of genetics would be like screenwriting. Follow the analogy so far? Good. The concept ofepigenetics, then, would be like directing. The script can be the same, but the director can choose to eliminate certain scenes or dialogue, altering the movie for better or worse. After all, Steven Spielbergs finished product would be drastically different than Woody Allens forthe same movie script, wouldnt it?

* Editors Note: Be wary of self-help claims that exploit epigenetics and seem too good to be true. We recommend you read about the abuseof epigenetics and pseudoscience.

Ready to learn epigenetics in further detail? Read on:Fundamentals of Epigenetics

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A Super Brief and Basic Explanation of Epigenetics for Total ...

The authors mother (right) and her twin are a study in difference and identity. Credit Photograph by Dayanita Singh for The New Yorker

On October 6, 1942, my mother was born twice in Delhi. Bulu, her identical twin, came first, placid and beautiful. My mother, Tulu, emerged several minutes later, squirming and squalling. The midwife must have known enough about infants to recognize that the beautiful are often the damned: the quiet twin, on the edge of listlessness, was severely undernourished and had to be swaddled in blankets and revived.

The first few days of my aunts life were the most tenuous. She could not suckle at the breast, the story runs, and there were no infant bottles to be found in Delhi in the forties, so she was fed through a cotton wick dipped in milk, and then from a cowrie shell shaped like a spoon. When the breast milk began to run dry, at seven months, my mother was quickly weaned so that her sister could have the last remnants.

Tulu and Bulu grew up looking strikingly similar: they had the same freckled skin, almond-shaped face, and high cheekbones, unusual among Bengalis, and a slight downward tilt of the outer edge of the eye, something that Italian painters used to make Madonnas exude a mysterious empathy. They shared an inner language, as so often happens with twins; they had jokes that only the other twin understood. They even smelled the same: when I was four or five and Bulu came to visit us, my mother, in a bait-and-switch trick that amused her endlessly, would send her sister to put me to bed; eventually, searching in the half-light for identity and differencefor the precise map of freckles on her faceI would realize that I had been fooled.

But the differences were striking, too. My mother was boisterous. She had a mercurial temper that rose fast and died suddenly, like a gust of wind in a tunnel. Bulu was physically timid yet intellectually more adventurous. Her mind was more agile, her tongue sharper, her wit more lancing. Tulu was gregarious. She made friends easily. She was impervious to insults. Bulu was reserved, quieter, and more brittle. Tulu liked theatre and dancing. Bulu was a poet, a writer, a dreamer.

Over the years, the sisters drifted apart. Tulu married my father in 1965 (he had moved to Delhi three years earlier). It was an arranged marriage, but also a risky one. My father was a penniless immigrant in a new city, saddled with a domineering mother and a half-mad brother who lived at home. To my mothers genteel West Bengali relatives, my fathers family was the embodiment of East Bengali hickdom: when his brothers sat down to lunch, they would pile their rice in a mound and punch a volcanic crater in it for gravy, as if marking the insatiable hunger of their village days. By comparison, Bulus marriage, also arranged, seemed a vastly safer prospect. In 1967, she married a young lawyer, the eldest son of a well-established clan in Calcutta, and moved to his familys sprawling, if somewhat decrepit, mansion.

By the time I was born, in 1970, the sisters fortunes had started to move in unexpected directions. Calcutta had begun its spiral into hell. Its economy was fraying, its infrastructure crumbling. Internecine political movements broke out frequently, closing streets and businesses for weeks. Between the citys cycles of violence and apathy, Bulus husband kept up the pretense of a job, leaving home every morning with the requisite briefcase and tiffin box, but who needed a lawyer in a city without laws? Eventually, the family sold the mildewing house, with its grand veranda and inner courtyard, and moved into a three-room flat.

My fathers fate mirrored that of his adoptive city. Delhi, the capital, was Indias overnourished child, fattened by subsidies, grants, and the nations aspirations to build a mega-metropolis. Our neighborhood, once girded by forests of thornbushes and overrun with wild dogs and goats, was soon transformed into one of the citys most affluent pockets of real estate. My family vacationed in Europe. We learned to eat with chopsticks, twisted our tongues around the word croissant, and swam in hotel pools. When the monsoons hit Calcutta, the mounds of garbage on the streets clogged the drains and turned the city into a vast, infested swamp. A stagnant pond, festering with mosquitoes, collected each year outside Bulus house. She called it her own swimming pool.

Why are identical twins alike? In the late nineteen-seventies, a team of scientists in Minnesota set out to determine how much these similarities arose from genes, rather than environmentsfrom nature, rather than nurture. Scouring thousands of adoption records and news clips, the researchers gleaned a rare cohort of fifty-six identical twins who had been separated at birth. Reared in different families and different cities, often in vastly dissimilar circumstances, these twins shared only their genomes. Yet on tests designed to measure personality, attitudes, temperaments, and anxieties, they converged astonishingly. Social and political attitudes were powerfully correlated: liberals clustered with liberals, and orthodoxy was twinned with orthodoxy. The same went for religiosity (or its absence), even for the ability to be transported by an aesthetic experience. Two brothers, separated by geographic and economic continents, might be brought to tears by the same Chopin nocturne, as if responding to some subtle, common chord struck by their genomes.

One pair of twins both suffered crippling migraines, owned dogs that they had named Toy, married women named Linda, and had sons named James Allan (although one spelled the middle name with a single l). Another pairone brought up Jewish, in Trinidad, and the other Catholic, in Nazi Germany, where he joined the Hitler Youthwore blue shirts with epaulets and four pockets, and shared peculiar obsessive behaviors, such as flushing the toilet before using it. Both had invented fake sneezes to diffuse tense moments. Two sistersseparated long before the development of languagehad invented the same word to describe the way they scrunched up their noses: squidging. Another pair confessed that they had been haunted by nightmares of being suffocated by various metallic objectsdoorknobs, fishhooks, and the like.

The Minnesota twin study raised questions about the depth and pervasiveness of qualities specified by genes: Where in the genome, exactly, might one find the locus of recurrent nightmares or of fake sneezes? Yet it provoked an equally puzzling converse question: Why are identical twins different? Because, you might answer, fate impinges differently on their bodies. One twin falls down the crumbling stairs of her Calcutta house and breaks her ankle; the other scalds her thigh on a tipped cup of coffee in a European station. Each acquires the wounds, calluses, and memories of chance and fate. But how are these changes recorded, so that they persist over the years? We know that the genome can manufacture identity; the trickier question is how it gives rise to difference.

David Allis, who has been studying the genomes face for identity and difference for three decades, runs a laboratory at Rockefeller University, in New York. For a scientist who has won virtually all of sciences most important prizes except the Nobel (and that has been predicted for years), Allis is ruthlessly self-effacingthe kind of person who offers to leave his name on a chit at the faculty lunchroom because he has forgotten his wallet in the office. (We know who you are, the woman at the cash register says, laughing.)

As a child, Allis grew up in the leeward shadow of his sister, a fraternal twin, in Cincinnati, Ohio. She was the studious one, the straight-A student; he was the popular kid, the high-school fraternity president casual about his schoolwork. We were similar but different, Allis said. At some point in college, though, Alliss studies became a calling rather than a chore. In 1978, having obtained a Ph.D. in biology at Indiana University, Allis began to tackle a problem that had long troubled geneticists and cell biologists: if all the cells in the body have the same genome, how does one become a nerve cell, say, and another a blood cell, which looks and functions very differently?

In the nineteen-forties, Conrad Waddington, an English embryologist, had proposed an ingenious answer: cells acquired their identities just as humans doby letting nurture (environmental signals) modify nature (genes). For that to happen, Waddington concluded, an additional layer of information must exist within a cella layer that hovered, ghostlike, above the genome. This layer would carry the memory of the cell, recording its past and establishing its future, marking its identity and its destiny but permitting that identity to be changed, if needed. He termed the phenomenon epigeneticsabove genetics. Waddington, ardently anti-Nazi and fervently Marxist, may have had more than a biological stake in this theory. The Nazis had turned a belief in absolute genetic immutability (a Jew is a Jew) into a state-mandated program of sterilization and mass murder. By affirming the plasticity of nature (everyone can be anyone), a Marxist could hope to eradicate such innate distinctions and achieve a radical collective good.

Waddingtons hypothesis was perhaps a little too inspired. No one had visualized a gene in the nineteen-forties, and the notion of a layer of information levitating above the genome was an abstraction built atop an abstraction, impossible to test experimentally. By the time I began graduate school, it had largely been forgotten, Allis said.

Had Allis started his experiments in the nineteen-eighties trying to pin down words like identity and memory, he might have found himself lost in a maze of metaphysics. But part of his scientific genius lies in radical simplification: he has a knack for boiling problems down to their tar. What allows a cell to maintain its specialized identity? A neuron in the brain is a neuron (and not a lymphocyte) because a specific set of genes is turned on and another set of genes is turned off. The genome is not a passive blueprint: the selective activation or repression of genes allows an individual cell to acquire its identity and to perform its function. When one twin breaks an ankle and acquires a gash in the skin, wound-healing and bone-repairing genes are turned on, thereby recording a scar in one body but not the other.

But what turns those genes on and off, and keeps them turned on or off? Why doesnt a liver cell wake up one morning and find itself transformed into a neuron? Allis unpacked the problem further: suppose he could find an organism with two distinct sets of genesan active set and an inactive setbetween which it regularly toggled. If he could identify the molecular switches that maintain one state, or toggle between the two states, he might be able to identify the mechanism responsible for cellular memory. What I really needed, then, was a cell with these properties, he recalled when we spoke at his office a few weeks ago. Two sets of genes, turned on or off by some signal.

Allis soon found his ideal subject: a bizarre single-celled microbe called Tetrahymena. Blob-shaped cells surrounded by dozens of tiny, whiskery projections called cilia, Tetrahymena are improbable-lookingeach a hairy Barbapapa, or a Mr. Potato Head who fell into a vat of Rogaine. Perhaps the strangest thing about this strange organism is that it carries two very distinct collections of genes, he told me. One is completely shut off during its normal life cycle and another is completely turned on. Its really black-and-white. Then, during reproduction, an entirely different nucleus wakes up and goes into action. So we could now ask, What signal, or mechanism, allows Tetrahymena to regulate one set of genes versus the next?

By the mid-nineteen-nineties, Allis had found an important clue. Genes are typically carried in long, continuous chains of DNA: one such chain can carry hundreds of thousands of genes. But a chain of DNA does not typically sit naked in animal cells; it is wrapped tightly around a core of proteins called histones. To demonstrate, Allis stood up from his desk, navigated his way through stacks of books and papers, and pointed at a model. A long plastic tube, cerulean blue, twisted sinuously around a series of white disks, like a python coiled around a skewer of marshmallows.

Histones had been known as part of the inner scaffold for DNA for decades, Allis went on. But most biologists thought of these proteins merely as packaging, or stuffing, for genes. When Allis gave scientific seminars in the early nineties, he recalled, skeptics asked him why he was so obsessed with the packing material, the stuff in between the DNA. His protozoan studies supplied an answer. In Tetrahymena, the histones did not seem passive at all, he said. The genes that were turned on were invariably associated with one form of histone, while the genes that were turned off were invariably associated with a different form of histone. A skein of silk tangled into a ball has very different properties from that same skein extended; might the coiling or uncoiling of DNA change the activity of genes?

In 1996, Allis and his research group deepened this theory with a seminal discovery. We became interested in the process of histone modification, he said. What is the signal that changes the structure of the histone so that DNA can be packed into such radically different states? We finally found a protein that makes a specific chemical change in the histone, possibly forcing the DNA coil to open. And when we studied the properties of this protein it became quite clear that it was also changing the activity of genes. The coils of DNA seemed to open and close in response to histone modificationsinhaling, exhaling, inhaling, like life.

Allis walked me to his lab, a fluorescent-lit space overlooking the East River, divided by wide, polished-stone benches. A mechanical stirrer, whirring in a corner, clinked on the edge of a glass beaker. Two features of histone modifications are notable, Allis said. First, changing histones can change the activity of a gene without affecting the sequence of the DNA. It is, in short, formally epi-genetic, just as Waddington had imagined. And, second, the histone modifications are passed from a parent cell to its daughter cells when cells divide. A cell can thus record memory, and not just for itself but for all its daughter cells.

By 2000, Allis and his colleagues around the world had identified a gamut of proteins that could modify histones, and so modulate the activity of genes. Other systems, too, that could scratch different kinds of code on the genome were identified (some of these discoveries predating the identification of histone modifications). One involved the addition of a chemical side chain, called a methyl group, to DNA. The methyl groups hang off the DNA string like Christmas ornaments, and specific proteins add and remove the ornaments, in effect decorating the genome. The most heavily methylated parts of the genome tend to be dampened in their activity.

In the ensuing decade, Allis wrote enormous, magisterial papers in which a rich cast of histone-modifying proteins appear and reappear through various roles, mapping out a hatchwork of complexity. (His twin, Cathy Allis, is an ace crossword-puzzle constructor, having supplied Times readers with nearly a hundred puzzlesan activity that is similar but different.) These protein systems, overlaying information on the genome, interacted with one another, reinforcing or attenuating their signals. Together, they generated the bewildering intricacy necessary for a cell to build a constellation of other cells out of the same genes, and for the cells to add memories to their genomes and transmit these memories to their progeny. Theres an epigenetic code, just like theres a genetic code, Allis said. There are codes to make parts of the genome more active, and codes to make them inactive.

And epigenetics could transform whole animals. The idea that cells can acquire profoundly different properties by manipulating their epigenome was becoming known, Danny Reinberg told me. But that you could create different forms of a creature out of the same genome using epigenetics? That was a real challenge.

Reinbergs lab is at New York Universitys School of Medicine. His office by the East River around Thirty-first Streetis like Alliss: another nest of books and offprints, a wide river view, and another model of DNA twisted around histones, although this room is filled with Reinbergs private botanical obsession: huge, overgrown succulents from other climes that assert themselves with a defiant muscularity. Intense, articulate, with a cultivated stubble, Reinberg resembles an athletea gymnast, or a wrestlerwhose skill depends on compaction and repetition. He grew up in Santiago, Chile, the child of parents who ran a jewelry business. He scored an A-minus in his first biochemistry class in college, in Valparaiso, but felt that he hadnt really mastered the material, so he applied to take the class again. The professor looked at him as if he were mad before relenting.

Like Allis, Reinberg became interested in epigenetics in the nineteen-nineties. He explored how modified histones were copied when a cell divides, right down to the molecular level. Allis described Reinbergs early work as some of the most elegant experiments in the field. But Reinberg sought a more advanced instance of epigenetic instructiona whole animal, not just a cell, whose form and identity could be shifted by shifting the epigenetic code. So imagine that you tighten some parts of the DNA and loosen other parts by changing the structures of the histones, Reinberg said. Can you change the form or nature of an animal simply by coiling and uncoiling various parts of its genome?

One blistering summer day in 2005, Reinberg found himself stuck in a van ferrying a group of scientists to an epigenetics meeting outside Mexico City. The traffic was jammed for mileshe shrugged, signalling South American resignationand I sat next to another scientist, Shelley Berger, whose work I had long admired, and we started talking. Berger, a molecular biologist who studies epigenetics at the University of Pennsylvania, had just returned from Costa Rica, where she had been looking at ant colonies.

Ants have a powerful caste system. A colony typically contains ants that carry out radically different roles and have markedly different body structures and behaviors. These roles, Reinberg learned, are often determined not by genes but by signals from the physical and social environment. Sibling ants, in their larval stage, become segregated into the different types based on environmental signals, he said. Their genomes are nearly identical, but the way the genes are usedturned on or off, and kept on or offmust determine what an ant becomes. It seemed like a perfect system to study epigenetics. And so Shelley and I caught a flight to Arizona to see Jrgen Liebig, the ant biologist, in his lab.

The collaboration between Reinberg, Berger, and Liebig has been explosively successfulthe sort of scientific story (two epigeneticists walk into a bar and meet an entomologist) that works its way into a legend. Carpenter ants, one of the species studied by the team, have elaborate social structures, with queens (bullet-size, fertile, winged), majors (bean-size soldiers who guard the colony but rarely leave it), and minors (nimble, grain-size, perpetually moving foragers). In a recent, revelatory study, researchers in Bergers lab injected a single dose of a histone-altering chemical into the brains of major ants. Remarkably, their identities changed; caste was recast. The major ants wandered away from the colony and began to forage for food. The guards turned into scouts. Yet the caste switch could occur only if the chemical was injected during a vulnerable period in the ants development.

Since 2012, Reinberg, continuing his partnership with Berger and Liebig, has been cultivating ant colonies in his own lab. One afternoon in April, I put on sky-blue sterile gloves and an apron, and accompanied a postdoctoral researcher in Reinbergs lab, Hua Yan, to the ant room. It is a neatly kept, gently lighted space with the slightly dank smell of sugar and dead maggotsant food. In a nightmarish inversion of an American picnic idyll, the ants live inside Tupperware containers, and the people watch from outside.

The most mature colonies in Reinbergs collection belong to a species called the jumping ant, a pugnacious social insect from southern India. Like most ant species, jumping ants segregate into castes. When the queen is removed from the colony, the workers, sensing opportunity, launch a vicious, fight-to-the-death campaign against one anotherstinging, biting, sparring, lopping off limbs and heads, until a few workers win and become queenlike. The behavior of these pseudo-queens, as Reinberg calls them, changes dramatically; their life spans increase. The pseudo-queen (the scientific term is gamergate, not to be confused with the vicious, fight-to-the-death campaign against female video-game-makers) acquires reproductive fecundity, and dominates the colony.

I looked through a transparent Tupperware lid at a teeming colony of jumping ants, and thought, inevitably, of the city around us. The workers scurried around the edges of the container with inexhaustible energy, gathering food and garbage. The gamergates, in contrast, moved lazily above their brood in the center of the container. The workers worked. The gamergates loungedwaking late, moving little. When a worker approached a gamergate, the dominant ant Tasered it with her antennae, warning the worker to keep off her royal territory. The worker retreated, its antennae lowered.

The remarkable thing about workers and gamergates, Yan told me, is that they are almost genetically identical. The gene sequence before and after the transition is the same. Yet, as DNA methyl groups or histone modifications get shifted around those gene sequences, the worker transforms into a gamergate, and virtually everything about the insects physiology and behavior changes. Were going to solve how the change can have such a dramatic effect on longevity, Reinberg said. Its like one twin that lives three times longer than the otherall by virtue of a change in epigenetic information.

The impact of the histone-altering experiment sank in as I left Reinbergs lab and dodged into the subway. (How could I resist the urge, that spring afternoon, to categorize the passengers on the No. 6 train into the three basic New Yorker archetypes: worker, soldier, queen?) All of an ants possible selves are inscribed in its genome. Epigenetic signals conceal some of these selves and reveal others, coiling some, uncoiling others. The ant chooses a life between its genes and its epigenesinhabiting one self among its incipient selves.

Epigeneticists, once a subcaste of biologist nudged to the far peripheries of the discipline, now find themselves firmly at its epicenter. Fifteen years ago, a meeting on cell biology would hold a session on histones or DNA methylationand no one would be at that session, Allis told me. Now there are meetings on the epigenetics of human memory, of ants, of cancer, of mental illness. Part of the reason for the excitement is that epigenes may be vastly more tractable than genes. Gene therapy was all the rage when I began my career, but manipulating genes has turned out to be much harder than envisioned, Allis said. Genes, after all, are the permanent repository of a cells information system, and thus more tamperproof. (If genes are hardware, epigenes are firmware.) But by altering epigenesthe manner in which DNA is coiled or uncoiled, methylated or demethylatedone should be able to alter which genes are activated.

Medical epigeneticists are most excited about the implications for cancer. In some cancers, such as leukemias, malignant cells have markedly aberrant patterns of DNA methylation or histone modification. Clearly, theres a signal that epigenetic information is important for a cancer cell, Allis said. But can a drug safely change the epigenome of a cancer cell without touching a normal cell? In my own leukemia- and lymphoma-focussed clinic, dozens of epigenetic drugs are on trial. Some alter methylation, while others perturb the histone-modification system. One woman with pre-leukemia had a spectacular remission on a drug called azacitidine, but, oddly, she began to have sudden spurts of anxiety. Were these symptoms related to the drugs effect on the epigenomes of brain cells?

Other researchers, following Reinberg and his colleagues, have looked at how epigenetics might change behaviorsnot just cellular memory and identity but an organisms memory and identity. The neuroscientist and psychiatrist Eric Nestler, who studies addiction, gave mice repeated injections of cocaine, and found that the histones were altered in the reward-recognizing region of the brain. When the histone modification was chemically blocked, the mice were less likely to become addicted. In 2004, a team of researchers at McGill University noticed that rats raised by low-nurturing mothers were likely to be notably stressed as young adults. The memory of childhood neglect in rats appears to be related to epigenetic changes: a gene that acts as a set point for stressan anxiety rheostatis dampened in these poorly nurtured rats, resulting in higher levels of stress hormones. McGill researchers went on to study the brains of human beings who were abused as children and later committed suicide, and found similar epigenetic alterations.

The medical impact of epigenetics remains to be established, but its biological influence has been evident for nearly a decade. Diffuse, mysterious observations, inexplicable by classical genetics, have epigenetic explanations at their core. When a female horse and a male donkey mate, they produce a longer-eared, thin-maned mule; a male horse and a female donkey typically generate a smaller, shorter-eared hinny. That a hybrids features depend on the precise configuration of male versus female parentage is impossible to explain unless the genes can remember whether they came from the mother or the fathera phenomenon called genomic imprinting. We now know that epigenetic notations etched in sperm and eggs underlie imprinted genes.

Perhaps the most startling demonstration of the power of epigenetics to set cellular memory and identity arises from an experiment performed by the Japanese stem-cell biologist Shinya Yamanaka in 2006. Yamanaka was taken by the idea that chemical marks attached to genes in a cell might function as a record of cellular identity. What if he could erase these marks? Would the adult cell revert to an original state and turn into an embryonic cell? He began his experiments with a normal skin cell from an adult mouse. After a decades-long hunt for identity-switching factors, he and his colleagues figured out a way to erase a cells memory. The process, they found, involved a cascade of events. Circuits of genes were activated or repressed. The metabolism of the cell was reset. Most important, epigenetic marks were erased and rewritten, resetting the landscape of active and inactive genes. The cell changed shape and size. Its wrinkles unmarked, its stiffening joints made supple, its youth restored, the cell could now become any cell type in the body. Yamanaka had reversed not just cellular memory but the direction of biological time.

Its one thing to study epigenetic changes across the life of a single organism, or down a line of cells. The more tantalizing question is whether epigenetic messages can, like genes, cross from parents to their offspring.

The most suggestive evidence for such transgenerational transmission may come from a macabre human experiment. In September, 1944, amid the most vengeful phase of the Second World War, German troops occupying the Netherlands banned the export of food and coal to its northern parts. Acute famine followed, called the Hongerwinterthe hunger winter. Tens of thousands of men, women, and children died of malnourishment; millions suffered it and survived. Not surprisingly, the children who endured the Hongerwinter experienced chronic health issues. In the nineteen-eighties, however, a curious pattern emerged: when the children born to women who were pregnant during the famine grew up, they had higher rates of morbidity as wellincluding obesity, diabetes, and mental illness. (Malnourishment in utero can cause the body to sequester higher amounts of fat in order to protect itself from caloric loss.) Methylation alterations were also seen in regions of their DNA associated with growth and development. But the oddest result didnt emerge for another generation. A decade ago, when the grandchildren of men and women exposed to the famine were studied, they, too, were reported to have had higher rates of illness. (These findings have been challenged, and research into this cohort continues.) Genes cannot change in an entire population in just two generations, Allis said. But some memory of metabolic stress could have become heritable.

Both Allis and Reinberg understand the implications of transgenerational epigenetic transmission: it would overturn fundamental principles of biology, including our understanding of evolution. Conceptually, a key element of classical Darwinian evolution is that genes do not retain an organisms experiences in a permanently heritable manner. Jean-Baptiste Lamarck, in the early nineteenth century, had supposed that when an antelope strained its neck to reach a tree its efforts were somehow passed down and its progeny evolved into giraffes. Darwin discredited that model. Giraffes, he proposed, arose through heritable variation and natural selectiona tall-necked specimen appears in an ancestral tree-grazing animal, and, perhaps during a period of famine, this mutant survives and is naturally selected. But, if epigenetic information can be transmitted through sperm and eggs, an organism would seem to have a direct conduit to the heritable features of its progeny. Such a system would act as a wormhole for evolutiona shortcut through the glum cycles of mutation and natural selection.

My visit with Allis had ended on a cautionary note. Much about the transmission of epigenetic information across generations is unknown, and we should be careful before making up theories about the kind of information or memory that is transmitted, he told me. By bypassing the traditional logic of genetics and evolution, epigenetics can arouse fantasies about warp-speeding heredity: you can make your children taller by straining your neck harder. Such myths abound and proliferate, often dangerously. A childs autism, the result of genetic mutation, gets attributed to the emotional trauma of his great-grandparents. Mothers are being asked to minimize anxiety during their pregnancy, lest they taint their descendants with anxiety-ridden genes. Lamarck is being rehabilitated into the new Darwin.

These fantasies should invite skepticism. Environmental information can certainly be etched on the genome. But such epigenetic scratch marks are rarely, if ever, carried forward across generations. A man who loses a leg in an accident bears the imprint of that accident in his cells, wounds, and scars, but he does not bear children with shortened legs. A hundred and forty generations of circumcision have not made the procedure any shorter. Nor has the serially uprooted life of my family burdened me, or my children, with any wrenching sense of estrangement.

In the fall of 2013, Bulu travelled to the United States. I had not seen her for nearly a decade, and I drove out to Robbinsville, New Jersey, with my family to visit her. It was October 6th, the birthday that she shared with my mother. She had cooked my favorite mealshrimp curry, a signature Tulu dish, tangy with just a hint of bitterness from lime rindand the house smelled of the heady mixture of boiled shellfish, lime, and the floral brand of hair oil that both sisters preferred, my private madeleine. Bulus face was leaner and more angular than I remembered it, but when she smiled the angles rearranged themselves and softened into a distant evocation of my mothers.

We made our way to the park outside the house, while the kids played in the garden. The October light was oblique and sepulchral, a halo-endowing, New World light that does not exist in Delhi or Calcutta. There had been an uncomfortable irony in that Bulu, who loved adventure, had spent most of her life in the same stodgy city, while Tulu, an inveterate homebody, fussy about mattresses and food, had been dragged across the globe by my travel-obsessed father. I asked Bulu about her encounter with America, the adventure of it all.

Oh, but Ive been here so many times, she said, laughing. Every time Tulu took a trip abroad, I bought a guidebook and travelled, too. There was something about the remark that reminded me of my mother. It was almost rueful, although without the aftertaste of bitterness. She shared my mothers lightness about fatean equanimity that borders nobility but comes with no pride.

As we meandered through the park over fallen leaves, Bulu reminisced about how the vicissitudes of their lives had reshaped her and her sister in different ways, while I couldnt help noting how fiercely they had converged. In calculus, the first derivative of a curve at any point refers not to the position of the point but to its propensity to change its position; not where an object is but how it moves. This shared quality was the lasting link between my mother and her twin. Tulu and Bulu were no longer recognizably identicalbut they shared the first derivative of identity.

It is easy to think of twins as comedies of nature. The rhyming names, the matching sailor suits, the tomfoolery of mistaken identities, the two-places-at-the-same-time movie plotgenetics for gags. But twins often experience parts of their lives as tragedies of nature. My mother and her sister grew up in a walled garden, imagining each other not as friends or siblings but as alternate selves. They were separated not at birth but at marriage, as sisters often are. Jeta Tulur, sheta Bulur, my grandfather would say: What is Tulus is also Bulus. But that wistful phrase, a parents fantasy of perfect parity for his children, was absurd; how could it possibly last? The grief that twins experience as they drift apart in life is unique, but it abuts a general grief: if eternal sameness will not guarantee eternal closeness, then what hope is there for siblings, or parents, or lovers?

Why are twins different? Well, because idiosyncratic events are recorded through idiosyncratic marks in their bodies. If you sequence the genomes of a pair of identical twins every decade for fifty years, you get the same sequence over and over. But if you sequence the epigenomes of a pair of twins you find substantial differences: the pattern of epigenetic marks on the genomes of their various cells, virtually identical at the start of the experiment, diverges over time.

Chance eventsinjuries, infections, infatuations; the haunting trill of that particular nocturneimpinge on one twin and not on the other. Genes are turned on and off in response to these events, as epigenetic marks are gradually layered above genes, etching the genome with its own scars, calluses, and freckles. Prospero, raging against the deformed Caliban in The Tempest, describes him as a devil, a born devil, on whose nature/Nurture can never stick. Caliban is destined to remain a genetic automaton, a windup ghoulvastly more pathetic than anything human. He experiences the world, but he has no capacity to be changed by it; he has a genome that lacks an epigenome.

It is a testament to the unsettling beauty of the genome that it can make the real world stick. Hindu philosophers have long described the experience of being as a webjaal. Genes form the threads of the web; the detritus that adheres to it transforms every web into a singular being. An organisms individuality, then, is suspended between genome and epigenome. We call the miracle of this suspension fate. We call our responses to it choice. We call one such unique variant of one such organism a self.

A strange thing happened on the way out of Reinbergs ant room. One of the ants leaped out of the Tupperware box onto my shirt. There was a momentary commotionThey bite, Yan said, matter-of-factlyand then we found the ant on my shoulder, making a desperate break for my ear. Yan pulled out a pair of forceps and, after a few attempts, she was returned to the colony.

The retrieval had been masterfully delicate, but the ant was injured: a leg had been bruised, and she waddled lopsidedly for a while. The wound would heal, I knew, but a scar would remain. She had done it: she had made difference out of similarity. The clone was somehow no longer quite a clone. I watched her make her way back to the colonythe One That Almost Got Away, to be memorialized in song and verseuntil she vanished into the metropolis of soldiers, workers, and queens.

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Breakthroughs in Epigenetics - The New Yorker

Behavioral epigenetics is the field of study examining the role of epigenetics in shaping animal (including human) behaviour.[1] It is an experimental science that seeks to explain how nurture shapes nature,[2] where nature refers to biological heredity[3] and nurture refers to virtually everything that occurs during the life-span (e.g., social-experience, diet and nutrition, and exposure to toxins).[4] Behavioral epigenetics attempts to provide a framework for understanding how the expression of genes is influenced by experiences and the environment[5] to produce individual differences in behaviour,[6]cognition[2]personality,[7] and mental health.[8][9]

Epigenetic gene regulation involves changes other than to the sequence of DNA and includes changes to histones (proteins around which DNA is wrapped) and DNA methylation.[4][10] These epigenetic changes can influence the growth of neurons in the developing brain[11] as well as modify activity of the neurons in the adult brain.[12][13] Together, these epigenetic changes on neuron structure and function can have a marked influence on an organism's behavior.[1]

In biology, and specifically genetics, epigenetics is the study of heritable changes in gene activity which are not caused by changes in the DNA sequence; the term can also be used to describe the study of stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable.[14][15]

Examples of mechanisms that produce such changes are DNA methylation[16] and histone modification,[17] each of which alters how genes are expressed without altering the underlying DNA sequence. Gene expression can be controlled through the action of repressor proteins that attach to silencer regions of the DNA.

DNA methylation turns a gene "off" it results in the inability of genetic information to be read from DNA; removing the methyl tag can turn the gene back "on".[18][19]

Epigenetics has a strong influence on the development of an organism and can alter the expression of individual traits.[10] Epigenetic changes occur not only in the developing fetus, but also in individuals throughout the human life-span.[4][20] Because some epigenetic modifications can be passed from one generation to the next,[21] subsequent generations may be affected by the epigenetic changes that took place in the parents.[21]

The first documented example of epigenetics affecting behavior was provided by Michael Meaney and Moshe Szyf. While working at McGill University in Montral in 2004, they discovered that the type and amount of nurturing a mother rat provides in the early weeks of the rat's infancy determines how that rat responds to stress later in life.[4] This stress sensitivity was linked to a down-regulation in the expression of the glucocorticoid receptor in the brain. In turn, this down-regulation was found to be a consequence of the extent of methylation in the promoter region of the glucocorticoid receptor gene.[1] Immediately after birth, Meaney and Szyf found that methyl groups repress the glucocorticoid receptor gene in all rat pups, making the gene unable to unwind from the histone in order to be transcribed, causing a decreased stress response. Nurturing behaviours from the mother rat were found to stimulate activation of stress signalling pathways that remove methyl groups from DNA. This releases the tightly wound gene, exposing it for transcription. The glucocorticoid gene is activated, resulting in lowered stress response. Rat pups that receive a less nurturing upbringing are more sensitive to stress throughout their life-span.

This pioneering work in rodents has been difficult to replicate in humans because of a general lack of availability human brain tissue for measurement of epigenetic changes.[1]

In a small clinical study in humans published in 2008, epigenetic differences were linked to differences in risk-taking and reactions to stress in monozygotic twins.[22] The study identified twins with different life paths, wherein one twin displayed risk-taking behaviours, and the other displayed risk-averse behaviours. Epigenetic differences in DNA methylation of the CpG islands proximal to the DLX1 gene correlated with the differing behavior.[22] The authors of the twin study noted that despite the associations between epigenetic markers and differences personality traits, epigenetics cannot predict complex decision-making processes like career selection.[22]

Animal and human studies have found correlations between poor care during infancy and epigenetic changes that correlate with long-term impairments that result from neglect.[23][24][25]

Studies in rats have shown correlations between maternal care in terms of the parental licking of offspring and epigenetic changes.[23] A high level of licking results in a long-term reduction in stress response as measured behaviorally and biochemically in elements of the hypothalamic-pituitary-adrenal axis (HPA). Further, decreased DNA methylation of the glucocorticoid receptor gene were found in offspring that experienced a high level of licking; the glucorticoid receptor plays a key role in regulating the HPA.[23] The opposite is found in offspring that experienced low levels of licking, and when pups are switched, the epigenetic changes are reversed. This research provides evidence for an underlying epigenetic mechanism.[23] Further support comes from experiments with the same setup, using drugs that can increase or decrease methylation.[24] Finally, epigenetic variations in parental care can be passed down from one generation to the next, from mother to female offspring. Female offspring who received increased parental care (i.e., high licking) became mothers who engaged in high licking and offspring who received less licking became mothers who engaged in less licking.[23]

In humans, a small clinical research study showed the relationship between prenatal exposure to maternal mood and genetic expression resulting in increased reactivity to stress in offspring.[4] Three groups of infants were examined: those born to mothers medicated for depression with serotonin reuptake inhibitors; those born to depressed mothers not being treated for depression; and those born to non-depressed mothers. Prenatal exposure to depressed/anxious mood was associated with increased DNA methylation at the glucocorticoid receptor gene and to increased HPA axis stress reactivity.[23] The findings were independent of whether the mothers were being pharmaceutically treated for depression.[23]

Recent research has also shown the relationship of methylation of the maternal glucocorticoid receptor and maternal neural activity in response to mother-infant interactions on video.[26] Longitudinal follow-up of those infants will be important to understand the impact of early caregiving in this high-risk population on child epigenetics and behavior.

A 2010 review discusses the role of DNA methylation in memory formation and storage, but the precise mechanisms involving neuronal function, memory, and methylation reversal remain unclear.[27]

Studies in rodents have found that the environment exerts an influence on epigenetic changes related to cognition, in terms of learning and memory;[4]environmental enrichment correlated with increased histone acetylation, and verification by administering histone deacetylase inhibitors induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories.[1][28] Research has also linked learning and long-term memory formation to reversible epigenetic changes in the hippocampus and cortex in animals with normal-functioning, non-damaged brains.[1][29] In human studies, post-mortem brains from Alzheimer's patients show increased histone de-acetylase levels.[30][31]

Note: colored text contains article links.

Environmental and epigenetic influences seem to work together to increase the risk of addiction.[40] For example, environmental stress has been shown to increase the risk of substance abuse.[41] In an attempt to cope with stress, alcohol and drugs can be used as an escape.[42] Once substance abuse commences, however, epigenetic alterations may further exacerbate the biological and behavioural changes associated with addiction.[40]

Even short-term substance abuse can produce long-lasting epigenetic changes in the brain of rodents,[40] via DNA methylation and histone modification.[17] Epigenetic modifications have been observed in studies on rodents involving ethanol, nicotine, cocaine, amphetamine, methamphetamine and opiates.[4] Specifically, these epigenetic changes modify gene expression, which in turn increases the vulnerability of an individual to engage in repeated substance overdose in the future. In turn, increased substance abuse results in even greater epigenetic changes in various components of a rodent's reward system[40] (e.g., in the nucleus accumbens[43]). Hence, a cycle emerges whereby changes in the pleasure-reward areas contribute to the long-lasting neural and behavioural changes associated with the increased likelihood of addiction, the maintenance of addiction and relapse.[40] In humans, alcohol consumption has been shown to produce epigenetic changes that contribute to the increased craving of alcohol. As such, epigenetic modifications may play a part in the progression from the controlled intake to the loss of control of alcohol consumption.[44] These alterations may be long-term, as is evidenced in smokers who still possess nicotine-related epigenetic changes ten years after cessation.[45] Therefore, epigenetic modifications[40] may account for some of the behavioural changes generally associated with addiction. These include: repetitive habits that increase the risk of disease, and personal and social problems; need for immediate gratification; high rates of relapse following treatment; and, the feeling of loss of control.[46]

Evidence for related epigenetic changes has come from human studies involving alcohol,[47] nicotine, and opiate abuse. Evidence for epigenetic changes stemming from amphetamine and cocaine abuse derives from animal studies. In animals, drug-related epigenetic changes in fathers have also been shown to negatively affect offspring in terms of poorer spatial working memory, decreased attention and decreased cerebral volume.[48]

Epigenetic changes may help to facilitate the development and maintenance of eating disorders via influences in the early environment and throughout the life-span.[20]Pre-natal epigenetic changes due to maternal stress, behaviour and diet may later predispose offspring to persistent, increased anxiety and anxiety disorders. These anxiety issues can precipitate the onset of eating disorders and obesity, and persist even after recovery from the eating disorders.[49]

Epigenetic differences accumulating over the life-span may account for the incongruent differences in eating disorders observed in monozygotic twins. At puberty, sex hormones may exert epigenetic changes (via DNA methylation) on gene expression, thus accounting for higher rates of eating disorders in men as compared to women. Overall, epigenetics contribute to persistent, unregulated self-control behaviours related to the urge to binge.[20]

Epigenetic changes including hypomethylation of glutamatergic genes (i.e., NMDA-receptor-subunit gene NR3B and the promoter of the AMPA-receptor-subunit gene GRIA2) in the post-mortem human brains of schizophrenics are associated with increased levels of the neurotransmitter glutamate.[50] Since glutamate is the most prevalent, fast, excitatory neurotransmitter, increased levels may result in the psychotic episodes related to schizophrenia. Interestingly, epigenetic changes affecting a greater number of genes have been detected in men with schizophrenia as compared to women with the illness.[51]

Population studies have established a strong association linking schizophrenia in children born to older fathers.[52][53] Specifically, children born to fathers over the age of 35 years are up to three times more likely to develop schizophrenia.[53] Epigenetic dysfunction in human male sperm cells, affecting numerous genes, have been shown to increase with age. This provides a possible explanation for increased rates of the disease in men.[51][53][not in citation given] To this end, toxins[51][53] (e.g., air pollutants) have been shown to increase epigenetic differentiation. Animals exposed to ambient air from steel mills and highways show drastic epigenetic changes that persist after removal from the exposure.[54] Therefore, similar epigenetic changes in older human fathers are likely.[53] Schizophrenia studies provide evidence that the nature versus nurture debate in the field of psychopathology should be re-evaluated to accommodate the concept that genes and the environment work in tandem. As such, many other environmental factors (e.g., nutritional deficiencies and cannabis use) have been proposed to increase the susceptibility of psychotic disorders like schizophrenia via epigenetics.[53]

Evidence for epigenetic modifications for bipolar disorder is unclear.[55] One study found hypomethylation of a gene promoter of a prefrontal lobe enzyme (i.e., membrane-bound catechol-O-methyl transferase, or COMT) in post-mortem brain samples from individuals with bipolar disorder. COMT is an enzyme that metabolizes dopamine in the synapse. These findings suggest that the hypomethylation of the promoter results in over-expression of the enzyme. In turn, this results in increased degradation of dopamine levels in the brain. These findings provide evidence that epigenetic modification in the prefrontal lobe is a risk factor for bipolar disorder.[56] However, a second study found no epigenetic differences in post-mortem brains from bipolar individuals.[57]

The causes of major depressive disorder (MDD) are poorly understood from a neuroscience perspective.[58] The epigenetic changes leading to changes in glucocorticoid receptor expression and its effect on the HPA stress system discussed above, have also been applied to attempts to understand MDD.[59]

Much of the work in animal models has focused on the indirect downregulation of brain derived neurotrophic factor (BDNF) by over-activation of the stress axis.[60][61] Studies in various rodent models of depression, often involving induction of stress, have found direct epigenetic modulation of BDNF as well.[62]

Epigenetics may be relevant to aspects of psychopathic behaviour through methylation and histone modification.[63] These processes are heritable but can also be influenced by environmental factors such as smoking and abuse.[64] Epigenetics may be one of the mechanisms through which the environment can impact the expression of the genome.[65] Studies have also linked methylation of genes associated with nicotine and alcohol dependence in women, ADHD, and drug abuse.[66][67][68] It is probable that epigenetic regulation as well as methylation profiling will play an increasingly important role in the study of the play between the environment and genetics of psychopaths.[69]

A study of the brains of 24 suicide completers, 12 of whom had a history of child abuse and 12 who did not, found decreased levels of glucocorticoid receptor in victims of child abuse and associated epigenetic changes.[70]

Several studies have indicated DNA cytosine methylation linked to the social behavior of insects, such as honeybees and ants. In honeybees, when nurse bee switched from her in-hive tasks to out foraging, cytosine methylation marks are changing. When a forager bee was reversed to do nurse duties, the cytosine methylation marks were also reversed.[71] Knocking down the DNMT3 in the larvae changed the worker to queen-like phenotype.[72] Queen and worker are two distinguish castes with different morphology, behavior, and physiology. Studies in DNMT3 silencing also indicated DNA methylation may regulate gene alternative splicing and pre-mRNA maturation.[73]

Many researchers contribute information to the Human Epigenome Consortium.[74] The aim of future research is to reprogram epigenetic changes to help with addiction, mental illness, age related changes,[2] memory decline, and other issues.[1] However, the sheer volume of consortium-based data makes analysis difficult.[2] Most studies also focus on one gene.[75] In actuality, many genes and interactions between them likely contribute to individual differences in personality, behaviour and health.[76] As social scientists often work with many variables, determining the number of affected genes also poses methodological challenges. More collaboration between medical researchers, geneticists and social scientists has been advocated to increase knowledge in this field of study.[77]

Limited access to human brain tissue poses a challenge to conducting human research.[2] Not yet knowing if epigenetic changes in the blood and (non-brain) tissues parallel modifications in the brain, places even greater reliance on brain research.[74] Although some epigenetic studies have translated findings from animals to humans,[70] some researchers caution about the extrapolation of animal studies to humans.[1] One view notes that when animal studies do not consider how the subcellular and cellular components, organs and the entire individual interact with the influences of the environment, results are too reductive to explain behaviour.[76]

Some researchers note that epigenetic perspectives will likely be incorporated into pharmacological treatments.[8] Others caution that more research is necessary as drugs are known to modify the activity of multiple genes and may, therefore, cause serious side effects.[1] However, the ultimate goal is to find patterns of epigenetic changes that can be targeted to treat mental illness, and reverse the effects of childhood stressors, for example. If such treatable patterns eventually become well-established, the inability to access brains in living humans to identify them poses an obstacle to pharmacological treatment.[74] Future research may also focus on epigenetic changes that mediate the impact of psychotherapy on personality and behaviour.[23]

Most epigenetic research is correlational; it merely establishes associations. More experimental research is necessary to help establish causation.[78] Lack of resources has also limited the number of intergenerational studies.[2] Therefore, advancing longitudinal[77] and multigenerational, experience-dependent studies will be critical to further understanding the role of epigenetics in psychology.[5]

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Epigenetics simply ingenious

Epigenetics studies genetic effects not encoded in the DNA sequence of an organism, hence the prefix epi- (Greek: - over, outside of, around).[1][2] Such effects on cellular and physiological phenotypic traits may result from external or environmental factors that switch genes on and off and affect how cells express genes.[3][4] These alterations may or may not be heritable, although the use of the term epigenetic to describe processes that are heritable is controversial.[5]

The term also refers to the changes themselves: functionally relevant changes to the genome that do not involve a change in the nucleotide sequence. Examples of mechanisms that produce such changes are DNA methylation and histone modification, each of which alters how genes are expressed without altering the underlying DNA sequence. Gene expression can be controlled through the action of repressor proteins that attach to silencer regions of the DNA. These epigenetic changes may last through cell divisions for the duration of the cell's life, and may also last for multiple generations even though they do not involve changes in the underlying DNA sequence of the organism;[6] instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.[7]

One example of an epigenetic change in eukaryotic biology is the process of cellular differentiation. During morphogenesis, totipotent stem cells become the various pluripotent cell lines of the embryo, which in turn become fully differentiated cells. In other words, as a single fertilized egg cell the zygote continues to divide, the resulting daughter cells change into all the different cell types in an organism, including neurons, muscle cells, epithelium, endothelium of blood vessels, etc., by activating some genes while inhibiting the expression of others.[8]

The term epigenetics in its contemporary usage emerged in the 1990s, but for some years has been used in somewhat variable meanings.[3] A consensus definition of the concept of epigenetic trait as "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence" was formulated at a Cold Spring Harbor meeting in 2008.

The term epigenesis has a generic meaning "extra growth", taken directly from Koine Greek , used in English since the 17th century.[9]

From this, and the associated adjective epigenetic, the term epigenetics was coined by C. H. Waddington in 1942 as pertaining to epigenesis in parallel to Valentin Haecker's 'phenogenetics' (Pnogenetik).[10]Epigenesis in the context of biology refers to the differentiation of cells from their initial totipotent state in embryonic development.[11]

When Waddington coined the term the physical nature of genes and their role in heredity was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype; he used the phrase "epigenetic landscape" as a metaphor for biological development. Waddington held that cell fates were established in development much like a marble rolls down to the point of lowest local elevation.[12]

Waddington suggested visualising increasing irreversibility of cell type differentiation as ridges rising between the valleys where the marbles (cells) are travelling.[13] In recent times Waddington's notion of the epigenetic landscape has been rigorously formalized in the context of the systems dynamics state approach to the study of cell-fate.[14][15] Cell-fate determination is predicted to exhibit certain dynamics, such as attractor-convergence (the attractor can be an equilibrium point, limit cycle or strange attractor) or oscillatory.[15]

The term "epigenetic" has also been used in developmental psychology to describe psychological development as the result of an ongoing, bi-directional interchange between heredity and the environment.[16] Interactivist ideas of development have been discussed in various forms and under various names throughout the 19th and 20th centuries. An early version was proposed, among the founding statements in embryology, by Karl Ernst von Baer and popularized by Ernst Haeckel. A radical epigenetic view (physiological epigenesis) was developed by Paul Wintrebert. Another variation, probabilistic epigenesis, was presented by Gilbert Gottlieb in 2003.[17] This view encompasses all of the possible developing factors on an organism and how they not only influence the organism and each other, but how the organism also influences its own development.

The developmental psychologist Erik Erikson used the term epigenetic principle in his book Identity: Youth and Crisis (1968), and used it to encompass the notion that we develop through an unfolding of our personality in predetermined stages, and that our environment and surrounding culture influence how we progress through these stages. This biological unfolding in relation to our socio-cultural settings is done in stages of psychosocial development, where "progress through each stage is in part determined by our success, or lack of success, in all the previous stages."[18][19][20]

Robin Holliday defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms."[21] Thus epigenetic can be used to describe anything other than DNA sequence that influences the development of an organism.

The more recent usage of the word in science has a stricter definition. It is, as defined by Arthur Riggs and colleagues, "the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence."[22] The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" genetics; thus epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance.[23]

The term "epigenetics", however, has been used to describe processes which have not been demonstrated to be heritable such as histone modification; there are therefore attempts to redefine it in broader terms that would avoid the constraints of requiring heritability. For example, Sir Adrian Bird defined epigenetics as "the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states."[6] This definition would be inclusive of transient modifications associated with DNA repair or cell-cycle phases as well as stable changes maintained across multiple cell generations, but exclude others such as templating of membrane architecture and prions unless they impinge on chromosome function. Such redefinitions however are not universally accepted and are still subject to dispute.[5] The NIH "Roadmap Epigenomics Project," ongoing as of 2016, uses the following definition: "...For purposes of this program, epigenetics refers to both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable."[24]

In 2008, a consensus definition of the epigenetic trait, "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence", was made at a Cold Spring Harbor meeting.[25]

The similarity of the word to "genetics" has generated many parallel usages. The "epigenome" is a parallel to the word "genome", referring to the overall epigenetic state of a cell, and epigenomics refers to more global analyses of epigenetic changes across the entire genome.[24] The phrase "genetic code" has also been adaptedthe "epigenetic code" has been used to describe the set of epigenetic features that create different phenotypes in different cells. Taken to its extreme, the "epigenetic code" could represent the total state of the cell, with the position of each molecule accounted for in an epigenomic map, a diagrammatic representation of the gene expression, DNA methylation and histone modification status of a particular genomic region. More typically, the term is used in reference to systematic efforts to measure specific, relevant forms of epigenetic information such as the histone code or DNA methylation patterns.

Epigenetic changes modify the activation of certain genes, but not the genetic code sequence of DNA. The microstructure (not code) of DNA itself or the associated chromatin proteins may be modified, causing activation or silencing. This mechanism enables differentiated cells in a multicellular organism to express only the genes that are necessary for their own activity. Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime; however, if gene inactivation occurs in a sperm or egg cell that results in fertilization, then some epigenetic changes can be transferred to the next generation.[26] This raises the question of whether or not epigenetic changes in an organism can alter the basic structure of its DNA (see Evolution, below), a form of Lamarckism.

Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.

DNA damage can also cause epigenetic changes.[27][28][29] DNA damage is very frequent, occurring on average about 60,000 times a day per cell of the human body (see DNA damage (naturally occurring)). These damages are largely repaired, but at the site of a DNA repair, epigenetic changes can remain.[30] In particular, a double strand break in DNA can initiate unprogrammed epigenetic gene silencing both by causing DNA methylation as well as by promoting silencing types of histone modifications (chromatin remodeling - see next section).[31] In addition, the enzyme Parp1 (poly(ADP)-ribose polymerase) and its product poly(ADP)-ribose (PAR) accumulate at sites of DNA damage as part of a repair process.[32] This accumulation, in turn, directs recruitment and activation of the chromatin remodeling protein ALC1 that can cause nucleosome remodeling.[33] Nucleosome remodeling has been found to cause, for instance, epigenetic silencing of DNA repair gene MLH1.[22][34] DNA damaging chemicals, such as benzene, hydroquinone, styrene, carbon tetrachloride and trichloroethylene, cause considerable hypomethylation of DNA, some through the activation of oxidative stress pathways.[35]

Foods are known to alter the epigenetics of rats on different diets.[36] Some food components epigenetically increase the levels of DNA repair enzymes such as MGMT and MLH1[37] and p53.[38][39] Other food components can reduce DNA damage, such as soy isoflavones[40][41] and bilberry anthocyanins.[42]

Epigenetic research uses a wide range of molecular biologic techniques to further our understanding of epigenetic phenomena, including chromatin immunoprecipitation (together with its large-scale variants ChIP-on-chip and ChIP-Seq), fluorescent in situ hybridization, methylation-sensitive restriction enzymes, DNA adenine methyltransferase identification (DamID) and bisulfite sequencing. Furthermore, the use of bioinformatic methods is playing an increasing role (computational epigenetics).

Computer simulations and molecular dynamics approaches revealed the atomistic motions associated with the molecular recognition of the histone tail through an allosteric mechanism.[43]

Several types of epigenetic inheritance systems may play a role in what has become known as cell memory,[44] note however that not all of these are universally accepted to be examples of epigenetics.

Covalent modifications of either DNA (e.g. cytosine methylation and hydroxymethylation) or of histone proteins (e.g. lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, and lysine ubiquitination and sumoylation) play central roles in many types of epigenetic inheritance. Therefore, the word "epigenetics" is sometimes used as a synonym for these processes. However, this can be misleading. Chromatin remodeling is not always inherited, and not all epigenetic inheritance involves chromatin remodeling.[45]

Because the phenotype of a cell or individual is affected by which of its genes are transcribed, heritable transcription states can give rise to epigenetic effects. There are several layers of regulation of gene expression. One way that genes are regulated is through the remodeling of chromatin. Chromatin is the complex of DNA and the histone proteins with which it associates. If the way that DNA is wrapped around the histones changes, gene expression can change as well. Chromatin remodeling is accomplished through two main mechanisms:

Mechanisms of heritability of histone state are not well understood; however, much is known about the mechanism of heritability of DNA methylation state during cell division and differentiation. Heritability of methylation state depends on certain enzymes (such as DNMT1) that have a higher affinity for 5-methylcytosine than for cytosine. If this enzyme reaches a "hemimethylated" portion of DNA (where 5-methylcytosine is in only one of the two DNA strands) the enzyme will methylate the other half.

Although histone modifications occur throughout the entire sequence, the unstructured N-termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation, methylation, ubiquitylation, phosphorylation, sumoylation, ribosylation and citrullination. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 lysines of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally related to transcriptional competence.

One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because it normally has a positively charged nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge, thus loosening the DNA from the histone. When this occurs, complexes like SWI/SNF and other transcriptional factors can bind to the DNA and allow transcription to occur. This is the "cis" model of epigenetic function. In other words, changes to the histone tails have a direct effect on the DNA itself.

Another model of epigenetic function is the "trans" model. In this model, changes to the histone tails act indirectly on the DNA. For example, lysine acetylation may create a binding site for chromatin-modifying enzymes (or transcription machinery as well). This chromatin remodeler can then cause changes to the state of the chromatin. Indeed, a bromodomain a protein domain that specifically binds acetyl-lysine is found in many enzymes that help activate transcription, including the SWI/SNF complex. It may be that acetylation acts in this and the previous way to aid in transcriptional activation.

The idea that modifications act as docking modules for related factors is borne out by histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive heterochromatin). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein HP1 recruits HP1 to K9 methylated regions. One example that seems to refute this biophysical model for methylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional activation. Tri-methylation in this case would introduce a fixed positive charge on the tail.

It has been shown that the histone lysine methyltransferase (KMT) is responsible for this methylation activity in the pattern of histones H3 & H4. This enzyme utilizes a catalytically active site called the SET domain (Suppressor of variegation, Enhancer of zeste, Trithorax). The SET domain is a 130-amino acid sequence involved in modulating gene activities. This domain has been demonstrated to bind to the histone tail and causes the methylation of the histone.[46]

Differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently from acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the histone code, although the idea that histone state can be read linearly as a digital information carrier has been largely debunked. One of the best-understood systems that orchestrates chromatin-based silencing is the SIR protein based silencing of the yeast hidden mating type loci HML and HMR.

DNA methylation frequently occurs in repeated sequences, and helps to suppress the expression and mobility of 'transposable elements':[47] Because 5-methylcytosine can be spontaneously deaminated (replacing nitrogen by oxygen) to thymidine, CpG sites are frequently mutated and become rare in the genome, except at CpG islands where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. DNA methylation patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent DNA methyltransferases, DNMT1, DNMT3A, and DNMT3B, the loss of any of which is lethal in mice.[48] DNMT1 is the most abundant methyltransferase in somatic cells,[49] localizes to replication foci,[50] has a 1040-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).[51]

By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after DNA replication, and therefore is often referred to as the maintenance' methyltransferase.[52] DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.[48][53] To emphasize the difference of this molecular mechanism of inheritance from the canonical Watson-Crick base-pairing mechanism of transmission of genetic information, the term 'Epigenetic templating' was introduced.[54] Furthermore, in addition to the maintenance and transmission of methylated DNA states, the same principle could work in the maintenance and transmission of histone modifications and even cytoplasmic (structural) heritable states.[55]

Histones H3 and H4 can also be manipulated through demethylation using histone lysine demethylase (KDM). This recently identified enzyme has a catalytically active site called the Jumonji domain (JmjC). The demethylation occurs when JmjC utilizes multiple cofactors to hydroxylate the methyl group, thereby removing it. JmjC is capable of demethylating mono-, di-, and tri-methylated substrates.[56]

Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Epigenetic control is often associated with alternative covalent modifications of histones.[57] The stability and heritability of states of larger chromosomal regions are suggested to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes.[58] A simplified stochastic model for this type of epigenetics is found here.[59][60]

It has been suggested that chromatin-based transcriptional regulation could be mediated by the effect of small RNAs. Small interfering RNAs can modulate transcriptional gene expression via epigenetic modulation of targeted promoters.[61]

Sometimes a gene, after being turned on, transcribes a product that (directly or indirectly) maintains the activity of that gene. For example, Hnf4 and MyoD enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factor activity of the proteins they encode. RNA signalling includes differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development.[62] Other epigenetic changes are mediated by the production of different splice forms of RNA, or by formation of double-stranded RNA (RNAi). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are often turned on or off by signal transduction, although in some systems where syncytia or gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion. A large amount of RNA and protein is contributed to the zygote by the mother during oogenesis or via nurse cells, resulting in maternal effect phenotypes. A smaller quantity of sperm RNA is transmitted from the father, but there is recent evidence that this epigenetic information can lead to visible changes in several generations of offspring.[63]

MicroRNAs (miRNAs) are members of non-coding RNAs that range in size from 17 to 25 nucleotides. miRNAs regulate a large variety of biological functions in plants and animals.[64] So far, in 2013, about 2000 miRNAs have been discovered in humans and these can be found online in a miRNA database.[65] Each miRNA expressed in a cell may target about 100 to 200 messenger RNAs that it downregulates.[66] Most of the downregulation of mRNAs occurs by causing the decay of the targeted mRNA, while some downregulation occurs at the level of translation into protein.[67]

It appears that about 60% of human protein coding genes are regulated by miRNAs.[68] Many miRNAs are epigenetically regulated. About 50% of miRNA genes are associated with CpG islands,[64] that may be repressed by epigenetic methylation. Transcription from methylated CpG islands is strongly and heritably repressed.[69] Other miRNAs are epigenetically regulated by either histone modifications or by combined DNA methylation and histone modification.[64]

In 2011, it was demonstrated that the methylation of mRNA plays a critical role in human energy homeostasis. The obesity-associated FTO gene is shown to be able to demethylate N6-methyladenosine in RNA.[70][71]

sRNAs are small (50250 nucleotides), highly structured, non-coding RNA fragments found in bacteria. They control gene expression including virulence genes in pathogens and are viewed as new targets in the fight against drug-resistant bacteria.[72] They play an important role in many biological processes, binding to mRNA and protein targets in prokaryotes. Their phylogenetic analyses, for example through sRNAmRNA target interactions or protein binding properties, are used to build comprehensive databases.[73] sRNA-gene maps based on their targets in microbial genomes are also constructed.[74]

Prions are infectious forms of proteins. In general, proteins fold into discrete units that perform distinct cellular functions, but some proteins are also capable of forming an infectious conformational state known as a prion. Although often viewed in the context of infectious disease, prions are more loosely defined by their ability to catalytically convert other native state versions of the same protein to an infectious conformational state. It is in this latter sense that they can be viewed as epigenetic agents capable of inducing a phenotypic change without a modification of the genome.[75]

Fungal prions are considered by some to be epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. PSI+ and URE3, discovered in yeast in 1965 and 1971, are the two best studied of this type of prion.[76][77] Prions can have a phenotypic effect through the sequestration of protein in aggregates, thereby reducing that protein's activity. In PSI+ cells, the loss of the Sup35 protein (which is involved in termination of translation) causes ribosomes to have a higher rate of read-through of stop codons, an effect that results in suppression of nonsense mutations in other genes.[78] The ability of Sup35 to form prions may be a conserved trait. It could confer an adaptive advantage by giving cells the ability to switch into a PSI+ state and express dormant genetic features normally terminated by stop codon mutations.[79][80][81][82]

In ciliates such as Tetrahymena and Paramecium, genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.[83][84][85]

Eukaryotic genomes have numerous nucleosomes. Nucleosome position is not random, and determine the accessibility of DNA to regulatory proteins. This determines differences in gene expression and cell differentiation. It has been shown that at least some nucleosomes are retained in sperm cells (where most but not all histones are replaced by protamines). Thus nucleosome positioning is to some degree inheritable. Recent studies have uncovered connections between nucleosome positioning and other epigenetic factors, such as DNA methylation and hydroxymethylation [86]

Developmental epigenetics can be divided into predetermined and probabilistic epigenesis. Predetermined epigenesis is a unidirectional movement from structural development in DNA to the functional maturation of the protein. "Predetermined" here means that development is scripted and predictable. Probabilistic epigenesis on the other hand is a bidirectional structure-function development with experiences and external molding development.[87]

Somatic epigenetic inheritance, particularly through DNA and histone covalent modifications and nucleosome repositioning, is very important in the development of multicellular eukaryotic organisms.[86] The genome sequence is static (with some notable exceptions), but cells differentiate into many different types, which perform different functions, and respond differently to the environment and intercellular signalling. Thus, as individuals develop, morphogens activate or silence genes in an epigenetically heritable fashion, giving cells a memory. In mammals, most cells terminally differentiate, with only stem cells retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In mammals, some stem cells continue producing new differentiated cells throughout life, such as in neurogenesis, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Epigenetic modifications regulate the transition from neural stem cells to glial progenitor cells (for example, differentiation into oligodendrocytes is regulated by the deacetylation and methylation of histones.[88] Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin remodeling, it has been hypothesised that some kinds of plant cells do not use or require "cellular memories", resetting their gene expression patterns using positional information from the environment and surrounding cells to determine their fate.[89]

Epigenetic changes can occur in response to environmental exposurefor example, mice given some dietary supplements have epigenetic changes affecting expression of the agouti gene, which affects their fur color, weight, and propensity to develop cancer.[90][91]

Controversial results from one study suggested that traumatic experiences might produce an epigenetic signal that is capable of being passed to future generations. Mice were trained, using foot shocks, to fear a cherry blossom odor. The investigators reported that the mouse offspring had an increased aversion to this specific odor.[92][93] They suggested epigenetic changes that increase gene expression, rather than in DNA itself, in a gene, M71, that governs the functioning of an odor receptor in the nose that responds specifically to this cherry blossom smell. There were physical changes that correlated with olfactory (smell) function in the brains of the trained mice and their descendants. Several criticisms were reported, including the study's low statistical power as evidence of some irregularity such as bias in reporting results.[94] Due to limits of sample size, there is a probability that an effect will not be demonstrated to within statistical significance even if it exists. The criticism suggested that the probability that all the experiments reported would show positive results if an identical protocol was followed, assuming the claimed effects exist, is merely 0.4%. The authors also did not indicate which mice were siblings, and treated all of the mice as statistically independent.[95] The original researchers pointed out negative results in the paper's appendix that the criticism omitted in its calculations, and undertook to track which mice were siblings in the future.[96]

Epigenetics can affect evolution when epigenetic changes are heritable.[3] A sequestered germ line or Weismann barrier is specific to animals, and epigenetic inheritance is more common in plants and microbes. Eva Jablonka, Marion J. Lamb and tienne Danchin have argued that these effects may require enhancements to the standard conceptual framework of the modern synthesis and have called for an extended evolutionary synthesis.[97][98][99] Other evolutionary biologists have incorporated epigenetic inheritance into population genetics models and are openly skeptical, stating that epigenetic mechanisms such as DNA methylation and histone modification are genetically inherited under the control of natural selection.[100][101][102]

Two important ways in which epigenetic inheritance can be different from traditional genetic inheritance, with important consequences for evolution, are that rates of epimutation can be much faster than rates of mutation[103] and the epimutations are more easily reversible.[104] In plants heritable DNA methylation mutations are 100.000 times more likely to occur compared to DNA mutations.[105] An epigenetically inherited element such as the PSI+ system can act as a "stop-gap", good enough for short-term adaptation that allows the lineage to survive for long enough for mutation and/or recombination to genetically assimilate the adaptive phenotypic change.[106] The existence of this possibility increases the evolvability of a species.

More than 100cases of transgenerational epigenetic inheritance phenomena have been reported in a wide range of organisms, including prokaryotes, plants, and animals.[107] For instance, Mourning Cloak butterflies will change color through hormone changes in response to experimentation of varying temperatures.[108]

The filamentous fungus Neurospora crassa is a prominent model system for understanding the control and function of cytosine methylation. In this organisms, DNA methylation is associated with relics of a genome defense system called RIP (repeat-induced point mutation) and silences gene expression by inhibiting transcription elongation.[109]

The yeast prion PSI is generated by a conformational change of a translation termination factor, which is then inherited by daughter cells. This can provide a survival advantage under adverse conditions. This is an example of epigenetic regulation enabling unicellular organisms to respond rapidly to environmental stress. Prions can be viewed as epigenetic agents capable of inducing a phenotypic change without modification of the genome.[110]

Direct detection of epigenetic marks in microorganisms is possible with single molecule real time sequencing, in which polymerase sensitivity allows for measuring methylation and other modifications as a DNA molecule is being sequenced.[111] Several projects have demonstrated the ability to collect genome-wide epigenetic data in bacteria.[112][113][114][115]

While epigenetics is of fundamental importance in eukaryotes, especially metazoans, it plays a different role in bacteria. Most importantly, eukaryotes use epigenetic mechanisms primarily to regulate gene expression which bacteria rarely do. However, bacteria make widespread use of postreplicative DNA methylation for the epigenetic control of DNA-protein interactions. Bacteria also use DNA adenine methylation (rather than DNA cytosine methylation) as an epigenetic signal. DNA adenine methylation is important in bacteria virulence in organisms such as Escherichia coli, Salmonella, Vibrio, Yersinia, Haemophilus, and Brucella. In Alphaproteobacteria, methylation of adenine regulates the cell cycle and couples gene transcription to DNA replication. In Gammaproteobacteria, adenine methylation provides signals for DNA replication, chromosome segregation, mismatch repair, packaging of bacteriophage, transposase activity and regulation of gene expression.[110][116] There exists a genetic switch controlling Streptococcus pneumoniae (the pneumococcus) that allows the bacterium to randomly change its characteristics into six alternative states that could pave the way to improved vaccines. Each form is randomly generated by a phase variable methylation system. The ability of the pneumococcus to cause deadly infections is different in each of these six states. Similar systems exist in other bacterial genera.[117]

Epigenetics has many and varied potential medical applications.[118] In 2008, the National Institutes of Health announced that $190 million had been earmarked for epigenetics research over the next five years. In announcing the funding, government officials noted that epigenetics has the potential to explain mechanisms of aging, human development, and the origins of cancer, heart disease, mental illness, as well as several other conditions. Some investigators, like Randy Jirtle, PhD, of Duke University Medical Center, think epigenetics may ultimately turn out to have a greater role in disease than genetics.[119]

Direct comparisons of identical twins constitute an optimal model for interrogating environmental epigenetics. In the case of humans with different environmental exposures, monozygotic (identical) twins were epigenetically indistinguishable during their early years, while older twins had remarkable differences in the overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation.[3] The twin pairs who had spent less of their lifetime together and/or had greater differences in their medical histories were those who showed the largest differences in their levels of 5-methylcytosine DNA and acetylation of histones H3 and H4.[120]

Dizygotic (fraternal) and monozygotic (identical) twins show evidence of epigenetic influence in humans.[120][121][122] DNA sequence differences that would be abundant in a singleton-based study do not interfere with the analysis. Environmental differences can produce long-term epigenetic effects, and different developmental monozygotic twin subtypes may be different with respect to their susceptibility to be discordant from an epigenetic point of view.[123]

A high-throughput study, which denotes technology that looks at extensive genetic markers, focused on epigenetic differences between monozygotic twins to compare global and locus-specific changes in DNA methylation and histone modifications in a sample of 40 monozygotic twin pairs.[120] In this case, only healthy twin pairs were studied, but a wide range of ages was represented, between 3 and 74 years. One of the major conclusions from this study was that there is an age-dependent accumulation of epigenetic differences between the two siblings of twin pairs. This accumulation suggests the existence of epigenetic drift.

A more recent study, where 114 monozygotic twins and 80 dizygotic twins were analyzed for the DNA methylation status of around 6000 unique genomic regions, concluded that epigenetic similarity at the time of blastocyst splitting may also contribute to phenotypic similarities in monozygotic co-twins. This supports the notion that microenvironment at early stages of embryonic development can be quite important for the establishment of epigenetic marks.[124] Congenital genetic disease is well understood and it is clear that epigenetics can play a role, for example, in the case of Angelman syndrome and Prader-Willi syndrome. These are normal genetic diseases caused by gene deletions or inactivation of the genes, but are unusually common because individuals are essentially hemizygous because of genomic imprinting, and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.[125]

Some human disorders are associated with genomic imprinting, a phenomenon in mammals where the father and mother contribute different epigenetic patterns for specific genomic loci in their germ cells.[126] The best-known case of imprinting in human disorders is that of Angelman syndrome and Prader-Willi syndromeboth can be produced by the same genetic mutation, chromosome 15q partial deletion, and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father.[127] This is due to the presence of genomic imprinting in the region. Beckwith-Wiedemann syndrome is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.

Rett syndrome is underlain by mutations in the MECP2 gene despite no large-scale changes in expression of MeCP2 being found in microarray analyses. BDNF is downregulated in the MECP2 mutant resulting in Rett syndrome.

In the verkalix study, paternal (but not maternal) grandsons[128] of Swedish men who were exposed during preadolescence to famine in the 19th century were less likely to die of cardiovascular disease. If food was plentiful, then diabetes mortality in the grandchildren increased, suggesting that this was a transgenerational epigenetic inheritance.[129] The opposite effect was observed for femalesthe paternal (but not maternal) granddaughters of women who experienced famine while in the womb (and therefore while their eggs were being formed) lived shorter lives on average.[130]

A variety of epigenetic mechanisms can be perturbed in different types of cancer. Epigenetic alterations of DNA repair genes or cell cycle control genes are very frequent in sporadic (non-germ line) cancers, being significantly more common than germ line (familial) mutations in these sporadic cancers.[131][132] Epigenetic alterations are important in cellular transformation to cancer, and their manipulation holds great promise for cancer prevention, detection, and therapy.[133][134] Several medications which have epigenetic impact are used in several of these diseases. These aspects of epigenetics are addressed in cancer epigenetics.

Addiction is a disorder of the brain's reward system which arises through transcriptional and neuroepigenetic mechanisms and occurs over time from chronically high levels of exposure to an addictive stimulus (e.g., morphine, cocaine, sexual intercourse, gambling, etc.).[135][136][137][138] Transgenerational epigenetic inheritance of addictive phenotypes has been noted to occur in preclinical studies.[139][140]

Transgenerational epigenetic inheritance of anxiety-related phenotypes has been reported in a preclinical study using mice.[141] In this investigation, transmission of paternal stress-induced traits across generations involved small non-coding RNA signals transmitted via the male germline.

Epigenetic inheritance of depression-related phenotypes has also been reported in a preclinically.[141] Inheritance of paternal stress-induced traits across generations involved small non-coding RNA signals transmitted via the paternal germline.

The two forms of heritable information, namely genetic and epigenetic, are collectively denoted as dual inheritance. Members of the APOBEC/AID family of cytosine deaminases may concurrently influence genetic and epigenetic inheritance using similar molecular mechanisms, and may be a point of crosstalk between these conceptually compartmentalized processes.[142]

Fluoroquinolone antibiotics induce epigenetic changes in mammalian cells through iron chelation. This leads to epigenetic effects through inhibition of -ketoglutarate-dependent dioxygenases that require iron as a co-factor.[143]

Various pharmacological agents are applied for the production of induced pluripotent stem cells (iPSC) or maintain the embryonic stem cell (ESC) phenotypic via epigenetic approach. Adult stem cells like bone marrow stem cells have also shown a potential to differentiate into cardiac competent cells when treated with G9a histone methyltransferase inhibitor BIX01294.[144][145]

Due to the early stages of epigenetics as a science and to the sensationalism surrounding it, surgical oncologist David Gorski and geneticist Adam Rutherford caution against the drawing and proliferation of false and pseudoscientific conclusions from new age authors such as Deepak Chopra and Bruce Lipton.[146][147]

In Neal Stephensons 2015 novel Seveneves, survivors of a worldwide holocaust are tasked with seeding new life on a dormant Earth. Rather than create specific breeds of animals to be hunters, scavengers, or prey, species like canids are developed with mutable epigenetic traits, with the intention that the animals would quickly transform into the necessary roles that would be required for an ecosystem to rapidly evolve. Additionally, a race of humans, Moirans, are created to survive in space, with the hope that this subspecies of human would be able to adapt to unforeseeable dangers and circumstances, via an epigenetic process called "going epi".

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Epigenetics - Wikipedia

Epigenetics, the study of the chemical modification of specific genes or gene-associated proteins of an organism. Epigenetic modifications can define how the information in genes is expressed and used by cells. The term epigenetics came into general use in the early 1940s, when British embryologist Conrad Waddington used it to describe the interactions between genes and gene products, which direct development and give rise to an organisms phenotype (observable characteristics). Since then, information revealed by epigenetics studies has revolutionized the fields of genetics and developmental biology. Specifically, researchers have uncovered a range of possible chemical modifications to deoxyribonucleic acid (DNA) and to proteins called histones that associate tightly with DNA in the nucleus. These modifications can determine when or even if a given gene is expressed in a cell or organism.

The principal type of epigenetic modification that is understood is methylation (addition of a methyl group). Methylation can be transient and can change rapidly during the life span of a cell or organism, or it can be essentially permanent once set early in the development of the embryo. Other largely permanent chemical modifications also play a role; these include histone acetylation (addition of an acetyl group), ubiquitination (the addition of a ubiquitin protein), and phosphorylation (the addition of a phosphoryl group). The specific location of a given chemical modification can also be important. For example, certain histone modifications distinguish actively expressed regions of the genome from regions that are not highly expressed. These modifications may correlate with chromosome banding patterns generated by staining procedures common in karyotype analyses. Similarly, specific histone modifications may distinguish actively expressed genes from genes that are poised for expression or genes that are repressed in different kinds of cells.

It is clear that at least some epigenetic modifications are heritable, passed from parents to offspring in a phenomenon that is generally referred to as epigenetic inheritance, or passed down through multiple generations via transgenerational epigenetic inheritance. The mechanism by which epigenetic information is inherited is unclear; however, it is known that this information, because it is not captured in the DNA sequence, is not passed on by the same mechanism as that used for typical genetic information. Typical genetic information is encoded in the sequences of nucleotides that make up the DNA; this information is therefore passed from generation to generation as faithfully as the DNA replication process is accurate. Many epigenetic modifications, in fact, are spontaneously erased or reset when cells reproduce (whether by meiosis or mitosis), thereby precluding their inheritance.

Epigenetic changes not only influence the expression of genes in plants and animals but also enable the differentiation of pluripotent stem cells (cells having the potential to become any of many different kinds of cells). In other words, epigenetic changes allow cells that all share the same DNA and are ultimately derived from one fertilized egg to become specializedfor example, as liver cells, brain cells, or skin cells.

As the mechanisms of epigenetics have become better understood, researchers have recognized that the epigenomechemical modification at the level of the genomealso influences a wide range of biomedical conditions. This new perception has opened the door to a deeper understanding of normal and abnormal biological processes and has offered the possibility of novel interventions that might prevent or ameliorate certain diseases.

Epigenetic contributions to disease fall into two classes. One class involves genes that are themselves regulated epigenetically, such as the imprinted (parent-specific) genes associated with Angelman syndrome or Prader-Willi syndrome. Clinical outcomes in cases of these syndromes depend on the degree to which an inherited normal or mutated gene is or is not expressed. The other class involves genes whose products participate in the epigenetic machinery and thereby regulate the expression of other genes. For example, the gene MECP2 (methyl CpG binding protein 2) encodes a protein that binds to specific methylated regions of DNA and contributes to the silencing of those sequences. Mutations that impair the MECP2 gene can lead to Rett syndrome.

Many tumours and cancers are believed to involve epigenetic changes attributable to environmental factors. These changes include a general decrease in methylation, which is thought to contribute to the increased expression of growth-promoting genes, punctuated by gene-specific increases in methylation that are thought to silence tumour-suppressor genes. Epigenetic signaling attributed to environmental factors has also been associated with some characteristics of aging by researchers that studied the apparently unequal aging rates in genetically identical twins.

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One of the most promising areas of epigenetic investigation involves stem cells. Researchers have understood for some time that epigenetic mechanisms play a key role in defining the potentiality of stem cells. As those mechanisms become clearer, it may become possible to intervene and effectively alter the developmental state and even the tissue type of given cells. The implications of this work for future clinical regenerative intervention for conditions ranging from trauma to neurodegenerative disease are profound.

...and the yeast Saccharomyces cerevisiae, as well as for numerous microorganisms. Additional research during this time explored alternative mechanisms of inheritance, including epigenetic modification (the chemical modification of specific genes or gene-associated proteins), that could explain an organisms ability to transmit traits developed during its lifetime to its...

The term epigenetic is used to describe the dynamic interplay between genes and the environment during the course of development. The study of epigenetics highlights the complex nature of the relationship between the organisms genetic code, or genome, and the organisms directly observable physical and psychological manifestations and behaviours. In contemporary use, the term refers to...

unit of hereditary information that occupies a fixed position (locus) on a chromosome. Genes achieve their effects by directing the synthesis of proteins.

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epigenetics | Britannica.com

We used to think that a new embryo's epigenome was completely erased and rebuilt from scratch. But this isn't completely true. Some epigenetic tags remain in place as genetic information passes from generation to generation, a process called epigenetic inheritance.

Epigenetic inheritance is an unconventional finding. It goes against the idea that inheritance happens only through the DNA code that passes from parent to offspring. It means that a parent's experiences, in the form of epigenetic tags, can be passed down to future generations.

As unconventional as it may be, there is little doubt that epigenetic inheritance is real. In fact, it explains some strange patterns of inheritance geneticists have been puzzling over for decades.

Most complex organisms develop from specialized reproductive cells (eggs and sperm in animals). Two reproductive cells meet, then they grow and divide to form every type of cell in the adult organism. In order for this process to occur, the epigenome must be erased through a process called "reprogramming."

Reprogramming is important because eggs and sperm develop from specialized cells with stable gene expression profiles. In other words, their genetic information is marked with epigenetic tags. Before the new organism can grow into a healthy embryo, the epigenetic tags must be erased.

At certain times during development (the timing varies among species), specialized cellular machinery scours the genome and erases its epigenetic tags in order to return the cells to a genetic "blank slate." Yet, for a small minority of genes, epigenetic tags make it through this process and pass unchanged from parent to offspring.

Reprogramming resets the epigenome of the early embryo so that it can form every type of cell in the body. In order to pass to the next generation, epigenetic tags must avoid being erased during reprogramming.

In mammals, about 1% of genes escape epigenetic reprogramming through a process called Imprinting.

Epigenetic marks can pass from parent to offspring in a way that completely bypasses egg or sperm, thus avoiding the epigenetic purging that happens during early development.

Most of us were taught that our traits are hard-coded in the DNA that passes from parent to offspring. Emerging information about epigenetics may lead us to a new understanding of just what inheritance is.

Nurturing behavior in rats Rat pups who receive high or low nurturing from their mothers develop epigenetic differences that affect their response to stress later in life. When the female pups become mothers themselves, the ones that received high quality care become high nurturing mothers. And the ones that received low quality care become low nurturing mothers. The nurturing behavior itself transmits epigenetic information onto the pups' DNA, without passing through egg or sperm.

Gestational diabetes Mammals can experience a hormone-triggered type of diabetes during pregnancy, known as gestational diabetes. When the mother has gestational diabetes, the developing fetus is exposed to high levels of the sugar glucose. High glucose levels trigger epigenetic changes in the daughter's DNA, increasing the likelihood that she will develop gestational diabetes herself.

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There is no doubt that epigenetic inheritance occurs in plants and fungi. There is also a good case for epigenetic inheritance in invertebrates. While many researchers remain skeptical about the possibility of epigenetic inheritance in mammals, there is some evidence that it could be happening.

(Linaria vulgaris)

Common toadflax and peloric toadflax are identical in every way, except for the shape of their flowers. They are two variants of the same plant with a difference in one gene. But its not a difference in the DNA code. Its an epigenetic difference. And peloric toadflax can pass on this epimutation to its offspring.

(Raphanus raphanistrum)

When radish plants are attacked by caterpillars, they produce distasteful chemicals and grow protective spines. The offspring of caterpillar-damaged radishes also produce these defenses, even when they live in a caterpillar-free environment. The evidence of epigenetic inheritance in this case is indirect, though its highly likely that the information passes from parent to offspring through the reproductive cells.

(Daphnia)

Female water fleas respond to chemical signals from their predators by growing protective helmets. The offspring of helmeted water fleas are also born with helmets - even in the absence of predator signals. This effect continues to the next generation, though the helmets in the grandchildren are much smaller.

Vinclozolin is a fungicide commonly used on grape plants. Feeding vinclozolin to pregnant rats causes lifelong epigenetic changes in the pups. As adults, male offspring have low sperm counts, poor fertility, and a number of disease states including prostate and kidney disease. The great-grandsons of the exposed male pups also have low sperm counts.

Two lines of evidence in this case support epigenetic inheritance. First, the low sperm count persisted into the third generation. Second, the sperm had an abnormally high level of methyl tags (a type of epigenetic tag that usually silences genes). This is the best case for epigenetic inheritance in mammals to date (Feb 2009).

Making a case for epigenetic inheritance in humans remains especially challenging.

Humans have long life spans, making it time consuming to track multiple generations. Humans have greater genetic diversity than laboratory strains of animals, making it difficult to rule out genetic differences Ethical considerations limit the amount of experimental manipulation that can take place.

But we do have a few hints that suggest that it could be happening.

Geneticists analyzed 200 years worth of harvest records from a small town in Sweden. They saw a connection between food availability (large or small harvests) in one generation and the incidence of diabetes and heart disease in later generations.

The amount of food a grandfather had to eat between the ages of 9 and 12 was especially important. This is when boys go through the slow growth period (SGP), and form the cells that will give rise to sperm. As these cells form, the epigenome is copied along with the DNA. Since the building blocks for the epigenome come from the food a boy eats, his diet could impact how faithfully the epigenome is copied. The epigenome may represent a snapshot of the boys environment that can pass through the sperm to future generations.

Proving epigenetic inheritance is not always straightforward. To provide a watertight case for epigenetic inheritance, researchers must:

Researchers face the added challenge that epigenetic changes are transient by nature. That is, the epigenome changes more rapidly than the relatively fixed DNA code. An epigenetic change that was triggered by environmental conditions may be reversed when environmental conditions change again.

Three generations at once are exposed to the same environmental conditions (diet, toxins, hormones, etc.). In order to provide a convincing case for epigenetic inheritance, an epigenetic change must be observed in the 4th generation.

Epigenetic inheritance adds another dimension to the modern picture of evolution. The genome changes slowly, through the processes of random mutation and natural selection. It takes many generations for a genetic trait to become common in a population. The epigenome, on the other hand, can change rapidly in response to signals from the environment. And epigenetic changes can happen in many individuals at once. Through epigenetic inheritance, some of the experiences of the parents may pass to future generations. At the same time, the epigenome remains flexible as environmental conditions continue to change. Epigenetic inheritance may allow an organism to continually adjust its gene expression to fit its environment - without changing its DNA code.

Fish, E.W., Shahrokh, D., Bagot, R., Caldji, C., Bredy, T., Szyf, M., and Meaney, M.J. (2004).Epigenetic programming of stress responses through variations in maternal care. Annals of the New York Academy of Science 1036: 167-180 (subscription required).

Youngson, N.A. and Whitelaw, E. (2008).Transgenerational epigenetic effects. Annual Reviews in Genomics and Human Genetics 9: 233-57 (subscription required).

Kaati, G., Bygren, L.O., Pembrey, M., and Sjostrom, J. (2007).Transgenerational response to nutrition, early life circumstances and longevity. European Journal of Human Genetics 15: 784-790.

Chong, S., and Whitelaw, E. (2004).Epigenetic germline inheritance. Current Opinion in Genetics & Development. 14: 692-696 (subscription required).

APA format:

Genetic Science Learning Center. (2013, July 15) Epigenetics & Inheritance. Retrieved September 23, 2016, from http://learn.genetics.utah.edu/content/epigenetics/inheritance/

CSE format:

Epigenetics & Inheritance [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2013 [cited 2016 Sep 23] Available from http://learn.genetics.utah.edu/content/epigenetics/inheritance/

Chicago format:

Genetic Science Learning Center. "Epigenetics & Inheritance." Learn.Genetics.July 15, 2013. Accessed September 23, 2016. http://learn.genetics.utah.edu/content/epigenetics/inheritance/.

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Epigenetics & Inheritance

Epigenetics

PBS air date: July 24, 2007

CHEERFUL NEIL DEGRASSE TYSON: Did you ever notice that if you get to know two identical twins, they might look alike, but they're always subtly different?

CANTANKEROUS NEIL DEGRASSE TYSON: Yep, whatever.

CHEERFUL NEIL DEGRASSE TYSON: As they get older, those differences can get more pronounced. Two people start out the same but their appearance and their health can diverge. For instance, you have more gray hair.

CANTANKEROUS NEIL DEGRASSE TYSON: No. No, I don't. Identical twins have the same DNA, exact same genes.

CHEERFUL NEIL DEGRASSE TYSON: Yeah.

CANTANKEROUS NEIL DEGRASSE TYSON: And don't our genes make us who we are?

CHEERFUL NEIL DEGRASSE TYSON: Well they do, yes, but they're not the whole story. Some researchers have discovered a new bit of biology that can work with our genes or against them.

CANTANKEROUS NEIL DEGRASSE TYSON: Yeah, you're heavier, and I'm better looking.

CHEERFUL NEIL DEGRASSE TYSON: Yeah, whatever.

NEIL DEGRASSE TYSON: Imagine coming into the world with a person so like yourself, that for a time you don't understand mirrors.

CONCEPCIN: As a child, when I looked in the mirror I'd say, "That's my sister." And my mother would say, "No, that's your reflection!"

NEIL DEGRASSE TYSON: And even if you resist this cookie-cutter existence, cultivate individual styles and abilitieslike cutting your hair differently, or running fasteruncanny similarities bond you together: facial expressions, body language, the way you laughor dress for an interview, perhaps, when you hadn't a clue what your sister was going to wear. The synchrony in your lives constantly confronts you.

CLOTILDE: When I see my sister, I see myself. If she looks good, I think, "I look pretty today." But if she's not wearing makeup, I say, "My god, I look horrible!"

NEIL DEGRASSE TYSON: It's hardly surprising because you both come from the same egg. You have precisely the same genes. And you are literally clones, better known, as identical twins.

But now, imagine this: one day, your twin, your clone, is diagnosed with cancer. If you're the other twin, what can you do except wait for the symptoms?

CLOTILDE: I have been told that I am a high risk for cancer. Damocles' sword hangs over me.

NEIL DEGRASSE TYSON: And yet, it's not uncommon for a twin, like Ana Mari, to get a dread disease, while the other, like Clotilde, doesn't. But how can two people so alike, be so unalike?

Well, these mice may hold a clue. Their DNA is as identical as Ana Mari and Clotilde's despite the differences in their color and size. The human who studies them is Duke University's Randy Jirtle.

So, Randy, I see here you have skinny mice and fat mice. What have you done in this lab?

RANDY JIRTLE: Well, these animals are actually genetically identical.

NEIL DEGRASSE TYSON: The fat ones and the skinny ones?

RANDY JIRTLE: That's correct.

NEIL DEGRASSE TYSON: Because these are huge.

RANDY JIRTLE: They're huge.

NEIL DEGRASSE TYSON: Can we weigh them and find out?

RANDY JIRTLE: Sure. So if you take this...

NEIL DEGRASSE TYSON: It looks like they can barely walk.

RANDY JIRTLE: They can't walk too much. They're not going to be running very far. So that's about 63 grams.

NEIL DEGRASSE TYSON: 63 grams.

RANDY JIRTLE: Let's look at the other one.

NEIL DEGRASSE TYSON: So it's half the weight.

RANDY JIRTLE: Right.

NEIL DEGRASSE TYSON: This gets even more mysterious when you realize that these identical mice both have a particular gene, called agouti, but in the yellow mouse it stays on all the time, causing obesity.

Just look at this.

So what accounts for the thin mouse? Exercise? Atkins? No, a tiny chemical tag of carbon and hydrogen, called a methyl group, has affixed to the agouti gene, shutting it down. Living creatures possess millions of tags like these. Some, like methyl groups, attach to genes directly, inhibiting their function. Other types grab the proteins, called histones, around which genes coil, and tighten or loosen them to control gene expression. Distinct methylation and histone patterns exist in every cell, constituting a sort of second genome, the epigenome.

RANDY JIRTLE: Epigenetics literally translates into just meaning "above the genome." So if you would think, for example, of the genome as being like a computer, the hardware of a computer, the epigenome would be like the software that tells the computer when to work, how to work, and how much.

NEIL DEGRASSE TYSON: In fact, it's the epigenome that tells our cells what sort of cells they should be. Skin? Hair? Heart? You see, all these cells have the same genes. But their epigenomes silence the unneeded ones to make cells different from one another. Epigenetic instructions pass on as cells divide, but they're not necessarily permanent. Researchers think they can change, especially during critical periods like puberty or pregnancy.

Jirtle's mice reveal how the epigenome can be altered. To produce thin, brown mice instead of fat, yellow ones, he feeds pregnant mothers a diet rich in methyl groups to form the tags that can turn genes off.

RANDY JIRTLE: And I think you can see that we dramatically shifted the coat color and we get many, many more brown animals.

NEIL DEGRASSE TYSON: And that matters because your coat color is a tracer, is an indicator...

RANDY JIRTLE: That's correct.

NEIL DEGRASSE TYSON: ...of the fact that you have turned off that gene?

RANDY JIRTLE: That's right.

NEIL DEGRASSE TYSON: This epigenetic fix was also inherited by the next generation of mice, regardless of what their mothers ate. And when an environmental toxin was added to the diet instead of nutrients, more yellow babies were born, doomed to grow fat and sick like their mothers.

It seems to me, this has profound implications for our health.

RANDY JIRTLE: It does, for human health. If there are genes like this in humans, basically, what you eat can affect your future generations. So you're not only what you eat, but potentially what your mother ate, and possibly even what your grandparents ate.

NEIL DEGRASSE TYSON: So how do you go to humans to do this experiment, when you have these mice, and they're genetically identical on purpose?

RANDY JIRTLE: That's right.

NEIL DEGRASSE TYSON: So, who is your perfect lab human?

RANDY JIRTLE: Well, then we look for identical humans, which are identical twins.

NEIL DEGRASSE TYSON: Twins, twins.

And that brings us to the reason why we're showing you Spanish twins. In 2005, they participated in a groundbreaking study in Madrid. Its aim? To show just how identical, epigenetically, they are or aren't.

MANEL ESTELLER (Spanish National Cancer Center): One of the questions of twins is, "If my twin has this disease, I will have the same disease?" And genetics tell us that there is a high risk of developing the same disease. But it's not really sure they are going to have it, because our genes are just part of the story. Something has to regulate these genes, and part of the explanation is epigenetics.

NEIL DEGRASSE TYSON: Esteller wanted to see if the twins' epigenomes might account for their differences. To find out, he and his team collected cells from 40 pairs of identical twins, age three to 74, then began the laborious process of dissolving the cells until all that was left were wispy strands of DNA, the master molecule that contains our genes.

Next, researchers amplified fragments of the DNA, until the genes themselves became detectable. Those that had been turned off epigenetically appear as dark pink bands on the gel. Now, notice what happens when the genes from a pair of twins are cut out and overlapped.

The results are far from subtle, especially when you compare the epigenomes of two sets of twins that differ in age. Here, on the left, is the overlapped DNA of six-year-old Javier and Carlos. The yellow indicates where their gene expression is identical.

On the right, is the DNA of 66-year-old Ana Mari and Clotilde. In contrast to the younger twins, hardly any yellow shines through. Their epigenomes have changed dramatically.

The study suggests that, as twins age, epigenetic differences accumulate, especially when their lifestyles differ.

MANEL ESTELLER: One of the main findings of our research is that epigenomes can change in function of what we eat, of what we smoke, of what we drink. And this is one of the key differences between epigenetics and genetics.

NEIL DEGRASSE TYSON: As the chemical tags that control our genes change, cells can become abnormal, triggering diseases like cancer. Take a disorder like MDS, cancer of the blood and bone marrow. It's not a diagnosis you'd ever want to hear.

SANDRA SHELBY: When I went in, he started patting my hand, and he was going, "Your blood work does not look very good at all," and that I had MDS leukemia, and that there was not a cure for it. And, basically, I had six months to live.

NEIL DEGRASSE TYSON: Was epigenetics the reason? Could the silencing of critical genes turn normal cells into cancerous ones? It's scary to think that a few misplaced tags can kill you. But it's also good news, because we've traditionally viewed cancer as a disease stemming solely from broken genes. And it's a lot harder to fix damaged genes than to rearrange epigenetic tags. In fact, we already have a few drugs that will work. Recently, Sandra Shelby and Roy Cantwell participated in one of the first clinical trials using epigenetic therapy.

JEAN PIERRE ISSA (M.D. Anderson Cancer Center): The idea of epigenetic therapy is to stay away from killing the cell. Rather, what we are trying to do is diplomacy, trying to change the instructions of the cancer cells, reminding the cell, "Hey, you're a human cell. You shouldn't be behaving this way." And we try to do that by reactivating genes.

SANDRA SHELBY: The results have been incredible, and I didn't have really any horrible side effects.

ROY CANTWELL: I am in remission. And going in the plus direction is a whole lot better than the minus direction.

NEIL DEGRASSE TYSON: In fact, half the patients in the trial are now in remission. But, while it maybe easier to fix our epigenome than our genome, messing it up is easier, too.

RANDY JIRTLE: We've got to get people thinking more about what they do. They have a responsibility for their epigenome. Their genome they inherit. But their epigenome, they potentially can alter, and particularly that of their children. And that brings in responsibility, but it also brings in hope. You're not necessarily stuck with this. You can alter this.

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NOVA - Official Website | Epigenetics

What is Epigenetics?

As an organism grows and develops, carefully orchestrated chemical reactions activate and deactivate parts of the genome at strategic times and in specific locations. Epigenetics is the study of these chemical reactions and the factors that influence them.

The Epigenome at a Glance

Meet the epigenome and learn how it influences DNA.

Gene Control

Change the level of gene expression in a cell with the turn of a dial!

The Epigenome Learns From Its Experiences

Epigenetic tags record the gene-regulating signals the cell receives.

Epigenetics & Inheritance

Parents have a role in shaping the epigenomes of their offspring.

Genomic Imprinting

Certain genes are silenced during egg and sperm formation.

The epigenome dynamically responds to the environment. Stress, diet, behavior, toxins, and other factors regulate gene expression.

Insights From Identical Twins

Why do identical twins become more different as they age? See how the environment affects the epigenome in a pair of twins over time.

Lick Your Rats

What kind of mother are you? Care for a rat pup and shape its epigenome.

Nutrition & The Epigenome

What you eat can change your gene expression.

Epigenetics & The Human Brain

Epigenetic mechanisms play an important role both in normal brain function and in mental illness.

APA format:

Genetic Science Learning Center. (2013, July 15) Epigenetics. Retrieved August 05, 2016, from http://learn.genetics.utah.edu/content/epigenetics/

CSE format:

Epigenetics [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2013 [cited 2016 Aug 5] Available from http://learn.genetics.utah.edu/content/epigenetics/

Chicago format:

Genetic Science Learning Center. "Epigenetics." Learn.Genetics. July 15, 2013. Accessed August 5, 2016. http://learn.genetics.utah.edu/content/epigenetics/.

Originally posted here:
Learn Genetics - Epigenetics