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University of Connecticut Reverses Prader-Willi Syndrome in Lab by Restoring Silent Genes – Gilmore Health News

Posted: January 5, 2020 at 4:33 am

Discovery by UConn Health Researchers Could Mean Much for Prader-Willi Syndrome Treatment

Stem cell researchers at the University of Connecticut Health Center (UConn Health) have made a discovery that may significantly improve the treatment of people with Prader-Willi syndrome.

A child with PraderWilli Syndrome

In research published in Human Molecular Genetics, scientists reported that they were able to reverse this genetic disorder in brain cells growing in the lab. They achieved this by turning on genes that are usually silent in patients.

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Prader-Willi syndrome is typically the result of certain genes losing their functions. It develops when there is a deletion of a section of a chromosome a baby inherits from his father.

The disorder occurs in around one of every 15,000 births. It is the leading genetic cause of life-threatening obesity and has no cure.

Prader-Willi syndrome is not due to a defective gene. It is rather the outcome of a healthy gene that refuses to perform its role having been silenced. The gene becomes silent if only the copy inherited from the mother is present in a child.

The UConn Health researchers got rid of a protein responsible for the silencing in this study. As a result, there was an improvement in Prader-Willi syndrome.

The scientists observed that a particular protein caused the gene to become silent. This compound referred to as ZNF274 also plays a part in blocking some other gene types from expressing themselves.

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However, the protein appears to work alone in the case of this genetic disorder. It often acts together with another protein to silence other types of genes.

To find a way around the silencing of the gene inherited from a mother, the UConn Health researchers got stem cells from some Prader-Willi patients. They then proceeded to delete the ZNF274 protein from the area of the DNA involved in this disorder.

After the deletion, the research team stimulated the stem cells to grow into neurons or nerve cells. The neurons grew as normal to the expectation of the scientists. Most importantly, they expressed the silent gene inherited from the mother.

This discovery provides a direction for future research aimed at finding a cure for this genetic disorder. Studies have mostly focused on finding a treatment for certain symptoms linked to it.

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Symptoms associated with Prader-Willi syndrome include increased appetite and obesity, which can pose a serious threat to health. Short stature and intellectual disability are among other possible signs.

Interventions that can help to control these unpleasant symptoms can make so much difference in the life of a patient.

According to the UConn Health researchers, there are some other questions yet to answer regarding this discovery. For instance, it is not yet clear whether this approach can achieve the same effect directly in human brain cells. There is also a need to find out if it will work only in embryos, among other things.

Maeva Langouet, one of the UConn Health researchers, said there was still a need to find out whether deleting ZNF274 could lead to unwanted effects.

The post-doctoral fellow did express the hope that their findings may prove helpful to children with Prader-Willi syndrome in the future.

https://academic.oup.com/hmg/article/27/3/505/4708236

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University of Connecticut Reverses Prader-Willi Syndrome in Lab by Restoring Silent Genes - Gilmore Health News

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Molecular Genetics | ARUP Laboratories

Posted: August 7, 2018 at 7:43 pm

2007228 5-Fluorouracil (5-FU) Toxicity and Chemotherapeutic Response, 5 Mutations 5-Fluorouracil Sensitivity 5-FU, 5-Fluorouracil Toxicity and Chemotherapeutic Response Panel, Pharmacogenetics (PGx), Colorectal Cancer 2012166 Dihydropyrimidine Dehydrogenase (DPYD) Genotyping, 3 Mutations 5-Fluorouracil Sensitivity DYPD 5-Fluorouracil toxicity5-FU toxicity5-FU toxicity5FU toxicityAdrucil (DPYD) Genotyping, 3 MutationsXeloda (capecitabine) (DPYD) Genotyping, 3 Mutations DPDUftoral (tegafur/uracil) (DPYD) Genotyping, 3 Mutations 0051266 Achondroplasia (FGFR3) 2 Mutations Achondroplasia AD PCR, Skeletal Dysplasias, Neuroblastoma 0051265 Achondroplasia Mutation, Fetal Achondroplasia AD PCR FE, Skeletal Dysplasias 2011708 Alpha Globin (HBA1 and HBA2) Sequencing and Deletion/Duplication Alpha Thalassemia AG FGA, 2011622 Alpha Globin (HBA1 and HBA2) Deletion/Duplication Alpha Thalassemia HBA DD, Alpha thalassemia, alpha globin mutations, alpha globin gene analysis, A globin 0051495 Alpha Thalassemia (HBA1 & HBA2) 7 Deletions Alpha Thalassemia ALPHA THAL, Hemoglobinopathies 2002398 Alport Syndrome, X-linked (COL4A5) Sequencing and Deletion/Duplication Alport Syndrome ALPORT FGARenal disease, chronic kidney disease, hematuria 0051786 Alport Syndrome, X-linked (COL4A5) Sequencing Alport Syndrome ALPORT FGSRenal disease, chronic kidney disease, hematuria 2013341 Apolipoprotein E (APOE) Genotyping, Alzheimer Disease Risk Alzheimer's Disease APOE AZ 2005077 Angelman Syndrome and Prader-Willi Syndrome by Methylation Angelman Syndrome AS PWS, Angelman, Prader-Willi, Neurocognitive Impairments 2005564 Angelman Syndrome (UBE3A) Sequencing Angelman Syndrome UBE3A FGS 2012232 Angelman Syndrome and Prader-Willi Syndrome by Methylation, Fetal Angelman Syndrome AS PWS FE Prader-Labhart-Willi Syndrome, AS, PWS 2006540 Aortopathy Panel, Sequencing and Deletion/Duplication, 21 Genes Aortopathies AORT PANEL, Thoracic aortic aneurysms, dissections, familial thoracic TAAD AAT, ACTA2 (AAT6), FBN1, MYH11 (AAT4), MYLK (AAT7), SMAD3, TGFBR1 (AAT5), TGFBR2 (AAT3), SLC2A10, FBN2, COL3A1ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, MYH11, MYLK, PLOD1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFBR1, TGFBR2 2005584 Marfan Syndrome (FBN1) Sequencing and Deletion/Duplication Aortopathies FBN1 FGA 2005589 Marfan Syndrome (FBN1) Sequencing Aortopathies FBN1 FGS 2002705 TGFBR1 & TGFBR2 Sequencing Aortopathies LDS FGS, Loeys-Dietz, aortic aneurysm see Loeys-Dietz Syndrome Aortopathies see Marfan Syndrome and FBN1-Related Disorders Aortopathies 0055654 Apolipoprotein B Mutation Detection (G9775A, C9774T) Apolipoprotein B (APOB) APO B, Risk Markers - CVD (Non-traditional) 2013341 Apolipoprotein E (APOE) Genotyping, Alzheimer Disease Risk Apolipoprotein E (APOE) APOE AZ 2013337 Apolipoprotein E (APOE) Genotyping, Cardiovascular Risk Apolipoprotein E (APOE) APOE CR 0051415 Ashkenazi Jewish Diseases, 16 Genes Ashkenazi Jewish Panel (16 disorders) AJP, Jewish Genetic, Fanconi's, Fanconis,ABCC8, TMEM216, NEB, G6PC, DLD, BCKDHB, CLRN1, PCDH15 2013725 ABCC8-Related Hyperinsulinism, 3 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013745 NEB-Related Nemaline Myopathy, 1 Variant Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 0051433 Bloom Syndrome (BLM),1 Variant Ashkenazi Jewish Panel (16 disorders) BLM, Jewish Genetic 0051453 Canavan Disease (ASPA), 4 Variants Ashkenazi Jewish Panel (16 disorders) ASPA, Jewish Genetic 0051463 Dysautonomia, Familial (IKBKAP), 2 Variants Ashkenazi Jewish Panel (16 disorders) IKBKAP, Jewish Genetic Disease 0051468 Fanconi Anemia Group C, (FANCC), 2 Variants Ashkenazi Jewish Panel (16 disorders) FANCC, Jewish, Ashkenazi, Fanconi's, Fanconis, carrier testing, DNA 0051438 Gaucher Disease (GBA), 8 Variants Ashkenazi Jewish Panel (16 disorders) GBA, Jewish Genetic, Glucocerebrosidase, Glucosylceramidase 2013740 Glycogen Storage Disease, Type 1A (G6PC), 9 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013909 Joubert Syndrome Type 2 (TMEM216), 1 Variant Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013735 Lipoamide Dehydrogenase Deficiency (DLD), 2 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013730 Maple Syrup Urine Disease, Type 1B (BCKDHB), 3 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 0051448 Mucolipidosis Type IV (MCOLN1), 2 Variants Ashkenazi Jewish Panel (16 disorders) MCOLN1, Jewish Genetic, lysosomal 0051458 Niemann-Pick, Type A (SMPD1), 4 Variants Ashkenazi Jewish Panel (16 disorders) SMPD1, Jewish Genetic, acid sphingomyelinase, ASM, NP-A, lysosomal storage, L302P, 1bp del fsP330, R496L, R608del 0051428 Tay-Sachs Disease (HEXA), 7 Variants Ashkenazi Jewish Panel (16 disorders) HEXA, Jewish Genetic, Hex A, GM2 gangliosidosis, hexosaminidase, lysosomal storage, delta 7.6kb, IVS9(+1)G>A, 1278insTATC, IVS12(+1)G>C, G269S, R247W, R249W 2013750 Usher Syndrome, Types 1F and 3 (PCDH15 and CLRN1), 2 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2014314 Autism and Intellectual Disability Comprehensive Panel Autism Creatine, epilepsy, amino acids, organic acids, mucopolysaccharidoses (MPS), MPS, acylcarnitine, mental retardation, Fragile X, microarray 0051614 Rett Syndrome (MECP2), Full Gene Analysis Autism RETT FGA, MECP2-related, Rett, atypical Rett, neonatal encephalopathy, PPM-X, neurocognitive impairments 2002470 PTEN-Related Disorders Sequencing and Deletion/Duplication Autism PTEN FGA, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2004935 CDKL5-Related Disorders (CDKL5) Sequencing and Deletion/Duplication Autism CDKL5 FGA, X-linked infantile spasm 2005077 Angelman Syndrome and Prader-Willi Syndrome by Methylation Autism AS PWS, Angelman, Prader-Willi, Neurocognitive Impairments 2005564 Angelman Syndrome (UBE3A) Sequencing Autism UBE3A FGS 2010117 Beta Globin (HBB) Sequencing and Deletion/Duplication Beta Globin BG FGA, Beta thalassemia, beta globin, HBB 0050388 Beta Globin (HBB) Sequencing, Fetal Beta Globin BG SEQ FE 0051422 Beta Globin (HBB) HbS, HbC, and HbE Mutations, Fetal Beta Globin HB SCE FE 0051700 Biotinidase Deficiency (BTD), 5 Mutations Biotinidase Deficiency BTD MUT, Multiple carboxylase 0051730 Biotinidase Deficiency (BTD) Sequencing Additional Technical Information Biotinidase Deficiency BTD FGS, Multiple carboxylase 0051368 Rh Genotyping D Antigen (RhD positive/negative and RhD copy number) Blood Genotyping RHD, Hemolytic Disease of the Newborn, fetal erythroblastosis, isoimmunization, alloimmune hemolytic 0050421 RhCc Antigen (RHCE) Genotyping Blood Genotyping RH C, Hemolytic Disease of the Newborn, fetal rhesus type, alloimmunization, alloantibodies, maternal-fetal Rh incompatibility 0050423 RhEe Antigen (RHCE) Genotyping Blood Genotyping RH E, Hemolytic Disease of the Newborn, fetal rhesus type, alloimmunization, alloantibodies, maternal-fetal Rh incompatibility 0051644 Kell K/k Antigen (KEL) Genotyping Blood Genotyping KEL, Hemolytic Disease of the Newborn, K/k, Kell/Cellano 0051433 Bloom Syndrome (BLM),1 Variant Bloom Syndrome BLM, Jewish Genetic 2012026 Breast and Ovarian Hereditary Cancer Panel, Sequencing and Deletion/Duplication, 20 Genes Breast Cancer BOCAPAN, Breast Cancer, Tumor Markers, FISH, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MEN1, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53 2011949 Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing and Deletion/Duplication Breast Cancer BRCA FGA, BRACA, HBOC 2011954 Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing Breast Cancer BRCA FGS, BRACA, HBOC 2002722 PTEN-Related Disorders Sequencing Breast Cancer PTEN FGS, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2002470 PTEN-Related Disorders Sequencing and Deletion/Duplication Breast Cancer PTEN FGA, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2009313 Li-Fraumeni (TP53) Sequencing and Deletion/Duplication Breast Cancer TP53 FGA, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2009302 Li-Fraumeni (TP53) Sequencing Breast Cancer TP53 FGS, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2008398 Peutz-Jeghers Syndrome (STK11) Sequencing and Deletion/Duplication Breast Cancer STK11, STK11 FGA, hamartomatous polyps, mucocutaneous hypergigmentation 2008394 Peutz-Jeghers Syndrome (STK11) Sequencing Breast Cancer STK11, STK11 FGS, hamartomatous polyps, mucocutaneous hypergigmentation 0051453 Canavan Disease (ASPA), 4 Variants Canavan Disease ASPA, Jewish Genetic 2012032 Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes Cancer, Hereditary CANCERPAN, Lynch syndrome, breast cancer, multiple endocrine neoplasia, melanoma, retinoblastoma, paraganglioma, Li-Fraumeni, familial adenomatous polyposis, Peutz-Jegher, HNPCC, inherited cancer, renal cancer, GI cancer, colorectal cancer, NGS cancer panel 2010183 Cardiomyopathy and Arrhythmia Panel, Sequencing (85 Genes) and Deletion/Duplication (83 Genes) Cardiomyopathy CARDIACPAN, Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM), Arrhythmogenic right vernticular cardiomyopathy (ARVC), Left ventricular noncompaction (LVNC), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS), Long QT syndrome (LQTS), Romano-Ward, Short QT syndrome (SQTS), ABCC9, ACTC1, ACTN2, AKAP9, ANK2, ANKRD1, CACNA1C, CACNB2, CASQ2, CAV3, CORIN, COX15, CSRP3, CTF1, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FKRP, FKTN, FXN, GAA, GLA, GPD1L, ILK, JPH2, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNQ1, KLHL3, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYH10, MYL2, MYL3, MYLK2, MYOT, MYOZ2, MYPN, NEXN, OBSCN, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SCO2, SGCA, SGCB, SGCD, SGCG, SLC25A4, SNTA1, SYNE1, TAZ, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRPM4, TTN, TTR, VCLABCC9, ACTC1, ACTN2, AKAP9, ANK2, ANKRD1, CACNA1C, CACNB2, CASQ2, CAV3, CORIN, COX15, CSRP3, CTF1, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FKRP, FKTN, FXN, GAA, GLA, GPD1L, ILK, JPH2, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNQ1, KLHL3, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYH10, MYL2, MYL3, MYLK2, MYOT, MYOZ2, MYPN, NEXN, OBSCN, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SCO2, SGCA, SGCB, SGCD, SGCG, SLC25A4, SNTA1, SYNE1, TAZ, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRPM4, TTN, TTR, VCL, arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular noncompaction (LVNC), long QT syndrome (LQTS), Romano-Ward, short QT syndrome (SQTS) 2004203 Carnitine Deficiency, Primary (SLC22A5) Sequencing and Deletion/Duplication Carnitine Deficiency PCD FGA, OCTN2, carnitine uptake 0051682 Carnitine Deficiency, Primary (SLC22A5) Sequencing Carnitine Deficiency PCD FGS, OCTN2, carnitine uptake 0051415 Ashkenazi Jewish Diseases, 16 Genes Carrier Screening Panels AJP, Jewish Genetic, Fanconi's, Fanconis,ABCC8, TMEM216, NEB, G6PC, DLD, BCKDHB, CLRN1, PCDH15 3000258 Genetic Carrier Screen, (CF, FXS, and SMA) with Reflex to Methylation Carrier Screening Panels CF FX SMA 2014674 Expanded Carrier Screen Genotyping Carrier Screening Panels ECS GENO 2014671 Expanded Carrier Screen Genotyping with Fragile X Carrier Screening Panels ECS GEN FX 2014680 Expanded Carrier Screen by Next Generation Sequencing Carrier Screening Panels ECS SEQ 2014677 Expanded Carrier Screen by Next Generation Sequencing with Fragile X Carrier Screening Panels ECS SEQ FX 2004931 CDKL5-Related Disorders (CDKL5) Sequencing Additional Technical Information CDKL5-Related Disorders CDKL5 FGS, X-linked infantile spasm 2004935 CDKL5-Related Disorders (CDKL5) Sequencing and Deletion/Duplication CDKL5-Related Disorders CDKL5 FGA, X-linked infantile spasm 2005018 Celiac Disease (HLA-DQA1*05, HLA-DQB1*02, and HLA-DQB1*03:02) Genotyping Do not use in the initial evaluation for celiac disease. Useful in ruling out celiac disease (CD) (high negative predictive value) in selective clinical situations such as: Equivocal small-bowel histologic finding (Marsh I-II) in seronegative individuals Evaluation of individuals on a gluten-free diet (GFD) in whom no testing for CD was done before GFD Celiac Disease HLA CELIAC 2002965 Von Hippel-Lindau (VHL) Sequencing and Deletion/Duplication Central Nervous System Cancer VHL FGA, Brain Tumors, Pheochromocytoma 2002970 Von Hippel-Lindau (VHL) Sequencing Central Nervous System Cancer VHL FGS, Congenital polycythemia 2012032 Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes Central Nervous System Cancer CANCERPAN, Lynch syndrome, breast cancer, multiple endocrine neoplasia, melanoma, retinoblastoma, paraganglioma, Li-Fraumeni, familial adenomatous polyposis, Peutz-Jegher, HNPCC, inherited cancer, renal cancer, GI cancer, colorectal cancer, NGS cancer panel 2009313 Li-Fraumeni (TP53) Sequencing and Deletion/Duplication Central Nervous System Cancer TP53 FGA, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2009302 Li-Fraumeni (TP53) Sequencing Central Nervous System Cancer TP53 FGS, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2012160 Charcot-Marie-Tooth Type 1A (CMT1A)/Hereditary Neuropathy with Liability to Pressure Palsies (HNPP), PMP22 Deletion/Duplication Charcot-Marie-Tooth Disease CMT DD, AARS, AIFM1, ARHGEF10, ATL1, ATP7A, BAG3, BICD2, BSCL2, CCT5, DCTN1, DHTKD1, DNAJB2, DNM2,DNMT1, DYNC1H1, EGR2, FAM134B, FBLN5, FGD4, FIG4, GAN, GARS, GDAP1, GJB1, GNB4, HARS, HEXA, HINT1, HK1, HOXD10,HSPB1, HSPB3, HSPB8, IGHMBP2, IKBKAP, INF2, KARS, KIF1A, KIF1B, KIF5A, LAS1L, LITAF, LMNA, LRSAM1, MARS, MED25, MFN2,MPZ, MTMR2, MYH14, NDRG1, NEFL, NGF, NTRK1, PDK3, PLEKHG5, PMP22, PRNP, PRPS1, PRX, RAB7A, REEP1, SBF1, SBF2, SCN9A,SETX, SH3TC2, SLC12A6, SLC5A7, SOX10, SPTLC1, SPTLC2, TDP1, TFG, TRIM2, TRPV4, WNK1, YARS 2012155 Charcot-Marie-Tooth (CMT) and Related Hereditary Neuropathies, PMP22 Deletion/Duplication with Reflex to Sequencing Panel Charcot-Marie-Tooth Disease CMT REFLEX,AARS, AIFM1, ARHGEF10, ATL1, ATP7A, BAG3, BICD2, BSCL2, CCT5, DCTN1, DHTKD1, DNAJB2, DNM2,DNMT1, DYNC1H1, EGR2, FAM134B, FBLN5, FGD4, FIG4, GAN, GARS, GDAP1, GJB1, GNB4, HARS, HEXA, HINT1, HK1, HOXD10,HSPB1, HSPB3, HSPB8, IGHMBP2, IKBKAP, INF2, KARS, KIF1A, KIF1B, KIF5A, LAS1L, LITAF, LMNA, LRSAM1, MARS, MED25, MFN2,MPZ, MTMR2, MYH14, NDRG1, NEFL, NGF, NTRK1, PDK3, PLEKHG5, PMP22, PRNP, PRPS1, PRX, RAB7A, REEP1, SBF1, SBF2, SCN9A,SETX, SH3TC2, SLC12A6, SLC5A7, SOX10, SPTLC1, SPTLC2, TDP1, TFG, TRIM2, TRPV4, WNK1, YARS 2012151 Charcot-Marie-Tooth (CMT) and Related Hereditary Neuropathies Panel Sequencing Charcot-Marie-Tooth Disease CMT SEQ, AARS, AIFM1, ARHGEF10, ATL1, ATP7A, BAG3, BICD2, BSCL2, CCT5, DCTN1, DHTKD1, DNAJB2, DNM2,DNMT1, DYNC1H1, EGR2, FAM134B, FBLN5, FGD4, FIG4, GAN, GARS, GDAP1, GJB1, GNB4, HARS, HEXA, HINT1, HK1, HOXD10,HSPB1, HSPB3, HSPB8, IGHMBP2, IKBKAP, INF2, KARS, KIF1A, KIF1B, KIF5A, LAS1L, LITAF, LMNA, LRSAM1, MARS, MED25, MFN2,MPZ, MTMR2, MYH14, NDRG1, NEFL, NGF, NTRK1, PDK3, PLEKHG5, PMP22, PRNP, PRPS1, PRX, RAB7A, REEP1, SBF1, SBF2, SCN9A,SETX, SH3TC2, SLC12A6, SLC5A7, SOX10, SPTLC1, SPTLC2, TDP1, TFG, TRIM2, TRPV4, WNK1, YARS 2012609 CHARGE Syndrome, CHD7 Sequencing CHARGE Syndrome 2012717 CHARGE Syndrome (CHD7) Sequencing, Fetal CHARGE Syndrome 2002065 Chimerism, Recipient Pre-Transplant Chimerism STR-PRE 2002067 Chimerism, Donor Chimerism STR-DONOR 2002064 Chimerism, Post-Transplant, Sorted Cells Chimerism STR-POSTSC 2002066 Chimerism, Post-Transplant Chimerism STR-POST 3000544 Chronic Granulomatous Disease Panel (CYBB Sequencing and NCF1 Exon 2 GT Deletion) Chronic Granulomatous Disease CGD PAN, Cytochrome b-Positive, Type I, NCF1 Deficiency, Niemann-Pick Disease Type A, p47-PHOX, Soluble Oxidase Component II 3000541 Chronic Granulomatous Disease, X-Linked (CYBB) Sequencing Chronic Granulomatous Disease CYBB FGS , Cytochrome b-Positive, Type I, NCF1 Deficiency, Niemann-Pick Disease Type A, p47-PHOX, Soluble Oxidase Component II 2006366 Chronic Granulomatous Disease (NCF1) Exon 2 GT Deletion Chronic Granulomatous Disease NCF1, Cytochrome b-Positive, Type I, NCF1 Deficiency, Niemann-Pick Disease Type A, p47-PHOX, Soluble Oxidase Component II 2006261 Citrin Deficiency (SLC25A13) Sequencing Citrin Deficiency CITRIN FGSCitrin DeficiencyCitrullinemia Type II Failure to Thrive and Dyslipidemia Caused by Citrin Deficiency Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency 2007069 Citrullinemia, Type I (ASS1) Sequencing Citrullinemia, Type I 2011157 Cobalamin/Propionate/Homocysteine Metabolism Related Disorders Panel, Sequencing (25 Genes) and Deletion/Duplication (24 Genes) Cobalamin/Propionate/Homocysteine Metabolism Related Disorders VB12 PANEL, "ABCD4, ACSF3, AMN, CBS, CD320, CUBN, GIF, HCFC1, LMBRD1, MAT1A, MCEE, MMAA, MMAB, MMACHC, MMADHC, MTHFR, MTR, MTRR, MUT, PCCA, PCCB, SUCLA2, SUCLG1, TCN1, TCN2Methylmalonic aciduria and homocystinuria, cblJ typeCombined malonic and methylmalonic aciduriaMegaloblastic anemia-1, Norwegian typeHomocystinuria due to cystathionine beta-synthase deficiencyMethylmalonic aciduria due to transcobalamin receptor defectMegaloblastic anemia-1, Finnish typeIntrinsic factor deficiencyMethylmalonic acidemia and homocysteinemia, cblX type Methylmalonic aciduria and homocystinuria, cblF typeMethionine adenosyltransferase deficiencyMethylmalonyl-CoA epimerase deficiencyMethylmalonic aciduria, cblA typeMethylmalonic aciduria, cblB typeMethylmalonic aciduria and homocystinuria, cblC typeMethylmalonic aciduria and homocystinuria, cblD typeHomocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase activityHomocystinuria-megaloblastic anemia, cblG typeHomocystinuria-megaloblastic anemia, cbl E typeMethylmalonic aciduria due to methylmalonyl-CoA mutase deficiencyPropionic acidemiaMitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria)Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria)Transcobalamin I deficiencyTranscobalamin II deficiency 2013386 Congenital Adrenal Hyperplasia (CAH) (21-Hydroxylase Deficiency) Common Mutations Congenital Adrenal Hyperplasia (CAH) 2006220 Congenital Amegakaryocytic Thrombocytopenia (CAMT) Sequencing Congenital Amegakaryocytic Thrombocytopenia CAMT FGS, GeneDx 2008610 Creatine Transporter Deficiency (SLC6A8) Sequencing and Deletion/Duplication Creatine SLC6A8 FGA, SLC6A8-Related Creatine Transporter Deficiency, SLC6A8 Deficiency 2008615 Creatine Transporter Deficiency (SLC6A8) Sequencing Additional Technical Information Creatine SLC6A8 FGS, SLC6A8-Related Creatine Transporter Deficiency, SLC6A8 Deficiency 0051110 Cystic Fibrosis (CFTR) Sequencing Cystic Fibrosis CF-CFTR, Diagnostic, CF 0051640 Cystic Fibrosis (CFTR) Sequencing with Reflex to Deletion/Duplication Cystic Fibrosis CFTR FGA, Diagnostic, CF 2013661 Cystic Fibrosis (CFTR), 165 Pathogenic Variants Cystic Fibrosis CF VAR 2013662 Cystic Fibrosis (CFTR), 165 Pathogenic Variants, Fetal Cystic Fibrosis CF VAR FE 2013663 Cystic Fibrosis (CFTR), 165 Variants with Reflex to Sequencing Cystic Fibrosis CF VAR SEQ 2013664 Cystic Fibrosis (CFTR), 165 Variants with Reflex to Sequencing and Reflex to Deletion/Duplication Cystic Fibrosis CFVAR COMP 2014547 Cytochrome P450 2D6 (CYP2D6) 15 Variants and Gene Duplication Cytochrome P450 CYP 2D6, Tamoxifen, Pharmacogenetics (PGx), Schizophrenia, Breast Cancer, breast biomarkers 2012769 Cytochrome P450 2C19, CYP2C19 - 9 Variants Cytochrome P450 CYP2C19, Pharmacogenetics (PGx), Schizophrenia, Breast Cancer, breast biomarkers 2012766 Cytochrome P450 2C9, CYP2C9 - 2 Variants Additional Technical Information Cytochrome P450 CYP2C9, Warfarin Sensitivity, Pharmacogenetics (PGx) 2012740 Cytochrome P450 3A5 Genotyping, CYP3A5, 2 Variants Cytochrome P450 2013098 Cytochrome P450 Genotype Panel Cytochrome P450 CYP PAN 2006234 Diamond-Blackfan Anemia (RPL5) Sequencing Diamond-Blackfan Anemia RPL5 FGS, GeneDx 2006236 Diamond-Blackfan Anemia (RPL11) Sequencing Diamond-Blackfan Anemia RPL11 FGS 2006238 Diamond-Blackfan Anemia (RPS19) Sequencing Diamond-Blackfan Anemia RPS19 FGS 2011241 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication with Reflex to Sequencing Duchenne/Becker Muscular Dystrophy DMD REFLEX, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011235 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication Duchenne/Becker Muscular Dystrophy DMD DD, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011153 Duchenne/Becker Muscular Dystrophy (DMD) Sequencing Duchenne/Becker Muscular Dystrophy DMD SEQ, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011231 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication, Fetal Duchenne/Becker Muscular Dystrophy DMD DD FE, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2006244 Dyskeratosis Congenita, Autosomal (TERC) Sequencing Dyskeratosis Congenita TERC FGS, GeneDx 2006228 Dyskeratosis Congenita, X-linked (DKC1) Sequencing Dyskeratosis Congenita DKC1 FGS 2011241 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication with Reflex to Sequencing Dystrophinopathies DMD REFLEX, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011235 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication Dystrophinopathies DMD DD, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011153 Duchenne/Becker Muscular Dystrophy (DMD) Sequencing Dystrophinopathies DMD SEQ, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011231 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication, Fetal Dystrophinopathies DMD DD FE, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 0080351 Ehlers-Danlos Syndrome Type VI Screen, Urine Ehlers-Danlos Syndrome Type VI (Kyphoscoliotic Form) EDS6Ehlers-Danlos Syndrome, Kyphoscoliotic FormEDS Kyphoscoliotic FormEDS Type VIEDS VIEhlers-Danlos Syndrome Type VILysyl-Hydroxylase DeficiencyEhlers-Danlos Syndrome Type VIANevo SyndromePLOD1Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1EDSVIEDS6EDS 6 2005559 Ehlers-Danlos Syndrome Kyphoscoliotic Form, Type VI (PLOD1) Sequencing and Deletion/Duplication Ehlers-Danlos Syndrome Type VI (Kyphoscoliotic Form) EDS-VI FGA 2005360 Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing and Deletion/Duplication Endocrine Cancer MEN1 FGA, Multiple endocrine adenomatosis, Wermer syndrome, Multiple Endocrine Neoplasias (MEN) 2005359 Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing Endocrine Cancer MEN1 FGS, Multiple endocrine adenomatosis, Wermer syndrome, Multiple Endocrine Neoplasias (MEN) 0051390 Multiple Endocrine Neoplasia Type 2 (MEN2), RET Gene Mutations by Sequencing Endocrine Cancer MEN2 SEQ, Thyroid Cancer, Pheochromocytoma, Multiple Endocrine Neoplasias (MEN), MEN 2A, MEN 2B, familial medullary thyroid carcinoma, FMTC, RET proto-oncogene 2002965 Von Hippel-Lindau (VHL) Sequencing and Deletion/Duplication Endocrine Cancer VHL FGA, Brain Tumors, Pheochromocytoma 2002970 Von Hippel-Lindau (VHL) Sequencing Endocrine Cancer VHL FGS, Congenital polycythemia 2007167 Hereditary Paraganglioma-Pheochromocytoma (SDHB, SDHC, and SDHD) Sequencing and Deletion/Duplication Panel Endocrine Cancer 2012032 Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes Endocrine Cancer CANCERPAN, Lynch syndrome, breast cancer, multiple endocrine neoplasia, melanoma, retinoblastoma, paraganglioma, Li-Fraumeni, familial adenomatous polyposis, Peutz-Jegher, HNPCC, inherited cancer, renal cancer, GI cancer, colorectal cancer, NGS cancer panel 2006948 SDHB with Interpretation by Immunohistochemistry Endocrine Cancer 2011461 Hereditary Paraganglioma-Pheochromocytoma (SDHA) Sequencing Additional Technical Information Endocrine Cancer SDHA FGS 2007108 Hereditary Paraganglioma-Pheochromocytoma (SDHB) Sequencing and Deletion/Duplication Additional Technical Information Endocrine Cancer 2007117 Hereditary Paraganglioma-Pheochromocytoma (SDHC) Sequencing and Deletion/Duplication Additional Technical Information Endocrine Cancer 2002722 PTEN-Related Disorders Sequencing Endocrine Cancer PTEN FGS, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2007122 Hereditary Paraganglioma-Pheochromocytoma (SDHD) Sequencing and Deletion/Duplication Additional Technical Information Endocrine Cancer 2002470 PTEN-Related Disorders Sequencing and Deletion/Duplication Endocrine Cancer PTEN FGA, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2009313 Li-Fraumeni (TP53) Sequencing and Deletion/Duplication Endocrine Cancer TP53 FGA, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2009302 Li-Fraumeni (TP53) Sequencing Endocrine Cancer TP53 FGS, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2007533 Progressive Myoclonic Epilepsy (PME) Panel, Sequence Analysis and Exon-Level Deletion/Duplication Additional Technical Information Epilepsy PROG EPIL, seizures, PME, myoclonus, Lafora, Unverricht-Lundborg, neuronal ceroid lipofuscinoses, NCL, PRICKLE1, EPM2A, EPM2B, NHLRC1, CSTB, PPT1, CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN8, CLN10, TPP1, MFSD8, CTSD, GeneDx 2006069 Febrile Seizures Panel Epilepsy FEBRIL PAN 2007545 Childhood-Onset Epilepsy Panel, Sequencing and Deletion/Duplication Additional Technical Information Epilepsy CHILD EPIL, Early-onset epileptic encephalopathy, SCN1A, Sodium channel protein type 1 alpha, PCDH19, Protocadherin-19, SLC2A1, Solute carrier family 2, facilitated glucose transporter member 1, POLG, DNA polymerase subunit gamma-1, SCN2A, Sodium channel protein type 2 alpha, Generalized epilepsy with febrile seizures plus, GEFS+, SCN1A, Sodium channel protein type 1 alpha, SCN1B, Sodium channel subunit beta-1, GABRG2, Gamma-aminobutyric acid receptor subunit gamma-2, SCN2A, Sodium channel protein type 2 alpha, Juvenile Myoclonic Epilepsy, JME, EFHC1, EF-hand domain-containing protein 1, CACNB4, Voltage-dependent L-type calcium channel subunit beta-4, GABRA1, Gamma-aminobutyric acid receptor subunit alpha-1, Progressive Myoclonic Epilepsy, EPM2A, Laforin, NHLRC1, EPM2B, NHL repeat-containing protein 1, malin, CSTB, Cystatin-B, PRICKLE1, Prickle-like protein 1, Autosomal Dominant Focal Epilepsies, CHRNA4, Neuronal acetylcholine receptor alpha-4, CHRNB2, Neuronal acetylcholine receptor beta-2, CHRNA2, Neuronal acetylcholine receptor alpha-2, LGI1, Leucine-rich glioma-inactivated protein 1, atypical Rett syndromes, MECP2, Methyl CpG binding protein 2, CDKL5, Cyclin-dependent kinase-like 5, FOXG1, Forkhead box protein G1, Angelman, Angelman-like, Pitt-Hopkins, UBE3A, Ubiquitin protein ligase E3A, SLC9A6, Sodium/hydrogen exchanger 6, TCF4, Transcription factor 4, NRXN1, Neurexin-1, CNTNAP2, Contactin-associated protein-like 2, Mowat-Wilson, ZEB2, Zinc finger E-box-binding, homeobox 2, Creatine deficiency, GAMT, Guanidinoacetate N-methyltransferase, GATM, Glycine amidinotransferase, mitochondrial, Neuronal Ceroid Lipofuscinoses, NCL, PPT1, CLN1, Palmitoyl-protein thioesterase 1, TPP1, CLN2,Tripeptidyl-peptidase 1, CLN3, Battenin, CLN5, Ceroid-lipofuscinosis neuronal protein 5, CLN6, Ceroid-lipofuscinosis neuronal protein 6, MFSD8, CLN7, Major facilitator superfamily domain-containing protein 8, CLN8, Ceroid-lipofuscinosis neuronal protein 8, CTSD, CLN10, Cathepsin D, Adenosuccinate lyase deficiency, ADSL, Adenylosuccinate lyase, SYN1, Synapsin-1, Microcephaly with early-onset intractable seizures and developmental delay, MCSZ, PNK, Bifunctional polynucleotide, phosphatase/kinase, seizures, GeneDx 2007535 Infantile-Onset Epilepsy Panel, Sequencing and Deletion/Duplication Additional Technical Information Epilepsy INFANT EPIL; SCN1A; PCDH19; SLC2A1; POLG; SCN2A; SCN1A; SCN1B; GABRG2; EFHC1; CACNB4; GABRA1; EPM2A; NHLRC1; EPM2B; CSTB; PRICKLE1; CHRNA4; CHRNB2; CHRNA2; LGI1; MECP2; CDKL5; FOXG1; UBE3A; SLC9A6; TCF4; NRXN1; CNTNAP2; ZEB2; GAMT; GATM; PPT1; CLN1; TPP1; CLN2; CLN3; CLN5; CLN6; MFSD8; CLN7; CLN8; CTSD; CLN10; ADSL; SYN1; PNKP; benign familial neonatal seizures; generalized epilepsy with febrile seizures; juvenile myoclonic epilepsy; progressive myoclonic epilepsy; autosomal dominant focal epilepsies; Rett/atypical Rett syndromes; Angelman/Angelman-like/Pitt-Hopkins syndromes; Mowat-Wilson syndrome; creatine deficiency syndromes; neuronal ceroid lipofuscinoses; adenosuccinate lyase deficiency; epilepsy with variable learning and behavioral disorders; microcephaly with early onset intractable seizures and developmental delay", GeneDx 2006332 Exome Sequencing with Symptom-Guided Analysis Exome EXOME SEQ 2006336 Exome Sequencing Symptom-Guided Analysis, Patient Only Exome EXOSEQ PRO 0030192 APC Resistance Profile with Reflex to Factor V Leiden Factor V Leiden APC R, Venous thrombosis, Thromboembolism, Thrombophilia, clotting 0097720 Factor V Leiden (F5) R506Q Mutation Factor V Leiden FACV, Venous thrombosis, Thromboembolism, Thrombophilia, clotting 2001549 Factor V, R2 Mutation Factor V Leiden F5 R2, Venous thrombosis, Thromboembolism, Thrombophilia, clotting, A4070G 2003220 Factor XIII (F13A1) V34L Variant (assess thrombotic risk in Caucasians) Factor XIII (F13A1) V34L Variant FAC 13 MUT, Venous thrombosis, Thromboembolism, Thrombophilia, clotting 2004915 Familial Adenomatous Polyposis Panel: APC Sequencing, APC Deletion/Duplication, and MYH 2 Mutations Familial Adenomatous Polyposis FAP Panel, Familial Adenomatious Polyposis familial cancer, Colorectal Cancer, colon cancer, CRC, polyps, FAP, familial cancer 2004863 Familial Adenomatous Polyposis (APC) Sequencing Familial Adenomatous Polyposis APC FGS, Colorectal Cancer, colon cancer, CRC, polyps, Familial Adenomatious Polyposis FAP, familial cancer 2004911 MUTYH-Associated Polyposis (MUTYH) 2 Mutations Familial Adenomatous Polyposis MYH SEQ, Hereditary Colorectal Cancer, MAP, MUTH Associated Polyposis 2006191 MUTYH-Associated Polyposis (MUTYH) Sequencing Familial Adenomatous Polyposis MUTYH, FGS, MYH 2006307 MUTYH-Associated Polyposis (MUTYH) 2 Mutations with Reflex to Sequencing Familial Adenomatous Polyposis MUTYH RFLX MYH 0051463 Dysautonomia, Familial (IKBKAP), 2 Variants Familial Dysautonomia IKBKAP, Jewish Genetic Disease 2002658 Familial Mediterranean Fever (MEFV) Sequencing Familial Mediterranean Fever (MEFV) FMF FGS, DNA 2001961 Familial Mutation, Targeted Sequencing

The following genes are available:ACADVL, ACADM, ACVRL1, APC, ASS1, ATP7A, BMPR1A, BMPR2, BTD, CCM1, CCM2, CCM3, CDKL5, CFTR, COL4A5, CYP1B1, ENG, F8, F9, FBN1, G6PD, GALT, GJB2; HBA1, HBA2, HBB, INSR, LMNA, MECP2,MEFV, MEN1, MLH1, MSH2; MSH6, MUTYH, MYH3, NF1, OTC, PLOD1, PMS2; PRSS1, PTEN, PTPN11, RASA1, RET, SDHB, SDHC, SDHD, SLC22A5, SLC25A13, SMAD4, SPRED1, SPINK1, SOS1, STK11, TACI, TGFBR1, TGFBR2, UBE3A, VHL, VWF

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Epigenetics: Fundamentals, History, and Examples | What is …

Posted: July 9, 2018 at 2:44 pm

What is Epigenetics?

Epigenetics is the study of heritable changes in gene expression (active versus inactive genes) that do not involve changes to the underlying DNA sequence a change in phenotype without a change in genotype which in turn affects how cells read the genes. Epigenetic change is a regular and natural occurrence but can also be influenced by several factors including age, the environment/lifestyle, and disease state. Epigenetic modifications can manifest as commonly as the manner in which cells terminally differentiate to end up as skin cells, liver cells, brain cells, etc. Or, epigenetic change can have more damaging effects that can result in diseases like cancer. At least three systems including DNA methylation, histone modification and non-coding RNA (ncRNA)-associated gene silencing are currently considered to initiate and sustain epigenetic change. New and ongoing research is continuously uncovering the role of epigeneticsin a variety of human disorders and fatal diseases.

The Evolving Landscape of Epigenetic Research: A Brief History

What began as broad research focused on combining genetics and developmental biology by well-respected scientists including Conrad H. Waddington and Ernst Hadorn during the mid-twentieth century has evolved into the field we currently refer to as epigenetics. The term epigenetics, which was coined by Waddington in 1942, was derived from the Greek word epigenesis which originally described the influence of genetic processes on development. During the 1990s there became a renewed interest in genetic assimilation. This led to elucidation of the molecular basis of Conrad Waddingtons observations in which environmental stress caused genetic assimilation of certain phenotypic characteristics in Drosophila fruit flies. Since then, research efforts have been focused on unraveling the epigenetic mechanisms related to these types of changes.

Currently, DNA methylation is one of the most broadly studied and well-characterized epigenetic modifications dating back to studies done by Griffith and Mahler in 1969 which suggested that DNA methylation may be important in long term memory function. Other major modifications include chromatin remodeling, histone modifications, and non-coding RNA mechanisms. The renewed interest in epigenetics has led to new findings about the relationship between epigenetic changes and a host of disorders including various cancers, mental retardation associated disorders, immune disorders, neuropsychiatric disorders and pediatric disorders.

Epigenetics and the Environment: How Lifestyle Can Influence Epigenetic Change from One Generation to the Next

The field of epigenetics is quickly growing and with it the understanding that both the environment and individual lifestyle can also directly interact with the genome to influence epigenetic change. These changes may be reflected at various stages throughout a persons life and even in later generations. For example, human epidemiological studies have provided evidence that prenatal and early postnatal environmental factors influence the adult risk of developing various chronic diseases and behavioral disorders. Studies have shown that children born during the period of the Dutch famine from 1944-1945 have increased rates of coronary heart disease and obesity after maternal exposure to famine during early pregnancy compared to those not exposed to famine. Less DNA methylation of the insulin-like growth factor II (IGF2) gene, a well-characterized epigenetic locus, was found to be associated with this exposure. Likewise, adults that were prenatally exposed to famine conditions have also been reported to have significantly higher incidence of schizophrenia.

Research has also shown that a mothers exposure to pollution could impact her childs asthma susceptibilityand her intake of vitamin D could change DNA methylationthat influences placenta functioning. It doesnt stop at the mother, however, as further studies support that the father has a hand in his childs health and epigenetic marks as well. Read:A Childs Mental Fitness Could Be Epigenetically Influenced by Dads Diet.

How Lifestyle Can Affect Individual Epigenetics and Health

Although our epigenetic marks are more stable during adulthood, they are still thought to be dynamic and modifiable by lifestyle choices and environmental influence. It is becoming more apparent that epigenetic effects occur not just in the womb, but over the full course of a human life span, and that epigenetic changes could be reversed. There are numerous examples of epigenetics that show how different lifestyle choices and environmental exposures can alter marks on top of DNA and play a role in determining health outcomes.

The environment is being investigated as a powerful influence on epigenetic tags and disease susceptibility. Pollution has become a significant focus in this research area as scientists are finding that air pollution could alter methyl tags on DNA and increase ones risk for neurodegenerative disease. Interestingly, B vitamins may protect against harmful epigenetic effects of pollution and may be able to combat the harmful effects that particular matter has on the body.

Diet has also been shown to modify epigenetic tags in significant ways. The field of nutriepigenomics explores how food and epigenetics work together to influence health and wellbeing. For example, a study found that a high fat, low carb diet could open up chromatin and improve mental ability via HDAC inhibitors. Other studies have found that certain compounds within the foods we consume could protect again cancer by adjusting methyl marks on oncogenes or tumor suppressor genes. Ultimately, an epigenetic diet may guide people toward the optimal food regimen as scientific studies reveal the underlying mechanisms and impact that different foods have on the epigenome and health.

Explore these topics in epigenetics:

An accumulation of genetic and epigenetic errors can transform a normal cell into an invasive or metastatic tumor cell.

Cancer. Cancer was the first human disease to be linked to epigenetics. Studies performed by Feinberg and Vogelstein in 1983, using primary human tumor tissues, found that genes of colorectal cancer cells were substantially hypomethylated compared with normal tissues. DNA hypomethylation can activate oncogenes and initiate chromosome instability, whereas DNA hypermethylation initiates silencing of tumor suppressor genes. An accumulation of genetic and epigenetic errors can transform a normal cell into an invasive or metastatic tumor cell. Additionally, DNA methylation patterns may cause abnormal expression of cancer-associated genes. Global histone modification patterns are also found to correlate with cancers such as prostate, breast, and pancreatic cancer. Subsequently, epigenetic changes can be used as biomarkers for the molecular diagnosis of early cancer.

Mental Retardation Disorders. Epigenetic changes are also linked to several disorders that result in intellectual disabilities such as ATR-X, Fragile X, Rett, Beckwith-Weidman (BWS), Prader-Willi and Angelman syndromes. For example, the imprint disorders Prader-Willi syndrome and Angelman syndrome, display an abnormal phenotype as a result of the absence of the paternal or maternal copy of a gene, respectively. In these imprint disorders, there is a genetic deletion in chromosome 15 in a majority of patients. The same gene on the corresponding chromosome cannot compensate for the deletion because it has been turned off by methylation, an epigenetic modification. Genetic deletions inherited from the father result in Prader-Willi syndrome, and those inherited from the mother, Angelman syndrome.

Immunity & Related Disorders. There are several pieces of evidence showing that loss of epigenetic control over complex immune processes contributes to autoimmune disease. Abnormal DNA methylation has been observed in patients with lupus whose T cells exhibit decreased DNA methyltransferase activity and hypomethylated DNA. Disregulation of this pathway apparently leads to overexpression of methylation-sensitive genes such as the leukocyte function-associated factor (LFA1), which causes lupus-like autoimmunity. Interestingly, LFA1 expression is also required for the development of arthritis, which raises the possibility that altered DNA methylation patterns may contribute to other diseases displaying idiopathic autoimmunity. Epigenetic research has also shown that there is joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis, which could help explain why some targeted therapies for arthritis could alleviate pain in the knees but not the hips.

Neuropsychiatric Disorders. Epigenetic errors also play a role in the causation of complex adult psychiatric, autistic, and neurodegenerative disorders. Several reports have associated schizophrenia and mood disorders with DNA rearrangements that include the DNMT genes. DNMT1 is selectively overexpressed in gamma-aminobutyric acid (GABA)-ergic interneurons of schizophrenic brains, whereas hypermethylation has been shown to repress expression of Reelin (a protein required for normal neurotransmission, memory formation and synaptic plasticity) in brain tissue from patients with schizophrenia and patients with bipolar illness and psychosis. A role for aberrant methylation mediated by folate levels has been suggested as a factor in Alzheimers disease; also some preliminary evidence supports a model that incorporates both genetic and epigenetic contributions in the causation of autism. Autism has been linked to the region on chromosome 15 that is responsible for Prader-Willi syndrome and Angelman syndrome. Findings at autopsy of brain tissue from patients with autism have revealed a deficiency in MECP2 expression that appears to account for reduced expression of several relevant genes.

Pediatric Syndromes. In addition to epigenetic alterations, specific mutations affecting components of the epigenetic pathway have been identified that are responsible for several syndromes: DNMT3B in ICF (immunodeficiency, centromeric instability and facial anomalies) syndrome, MECP2 in Rett syndrome, ATRX in ATR-X syndrome (a-thalassemia/mental retardation syndrome, X-linked), and DNA repeats in facioscapulohumeral muscular dystrophy. In Rett syndrome, for example, MECP2 encodes a protein that binds to methylated DNA; mutations in this protein cause abnormal gene expression patterns within the first year of life. Girls with Rett syndrome display reduced brain growth, loss of developmental milestones and profound mental disabilities. Similarly, the ATR-X syndrome also includes severe developmental deficiencies due to loss of ATRX, a protein involved in maintaining the condensed, inactive state of DNA. Together, this constellation of clinical pediatric syndromes is associated with alterations in genes and chromosomal regions necessary for proper neurologic and physical development.

The increased knowledge of epigenetics, combined with rise of technologies such as CRISPR/Cas9 gene editing and next-generation sequencing in recent years, allows us to better understand the interplay between epigenetic change, gene regulation, and human diseases, and will lead to the development of new approaches for molecular diagnosis and targeted treatments across the clinical spectrum.

Ready to learn about the first epigenetic mechanism? Read on: DNA Methylation

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Epigenetics: Fundamentals, History, and Examples | What is ...

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Epigenetics – Wikipedia

Posted: October 20, 2016 at 1:43 am

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, 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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University of Connecticut Reverses Prader-Willi Syndrome in Lab by Restoring Silent Genes – Gilmore Health News

Molecular Genetics | ARUP Laboratories

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