Download PDF
Semin Reprod Med 2009; 27(5): 351-357
DOI: 10.1055/s-0029-1237423
© Thieme Medical Publishers

Epigenetics: Definition, Mechanisms and Clinical Perspective

Cathérine Dupont1 , 2 , D. Randall Armant1 , 3 , Carol A. Brenner1 , 2
  • 1Departments of Obstetrics & Gynecology, Wayne State University, Detroit, Michigan
  • 2Department of Physiology, School of Medicine, Wayne State University, Detroit, Michigan
  • 3Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
Further Information

Publication History

Publication Date:
26 August 2009 (online)

    Permissions and Reprints

ABSTRACT

A vast array of successive epigenetic modifications ensures the creation of a healthy individual. Crucial epigenetic reprogramming events occur during germ cell development and early embryogenesis in mammals. As highlighted by the large offspring syndrome with in vitro conceived ovine and bovine animals, any disturbance during germ cell development or early embryogenesis has the potential to alter epigenetic reprogramming. Therefore the complete array of human assisted reproductive technology (ART), starting from ovarian hormonal stimulation to embryo uterine transfer, could have a profound impact on the epigenetic state of human in vitro produced individuals. Although some investigators have suggested an increased incidence of epigenetic abnormalities in in vitro conceived children, other researchers have refuted these allegations. To date, multiple reasons can be hypothesized why irrefutable epigenetic alterations as a result of ART have not been demonstrated yet.

KEYWORDS

Epigenetics - X-chromosome inactivation - imprinting - transgenerational inheritance

REFERENCES

  • 1 Waddington C H. The epigenotype.  Endeavour. 1942;  1 18-20
    PubMedGoogle Scholar
  • 2 Waddington C H. The Basic Ideas of Biology. Towards a Theoretical Biology. Edinburgh, Scotland; Edinburgh University Press 1968: 1-32
    Google Scholar
  • 3 Wu Ct, Morris J R. Genes, genetics, and epigenetics: a correspondence.  Science. 2001;  293(5532) 1103-1105
    CrossrefPubMedGoogle Scholar
  • 4 Daskalos A, Nikolaidis G, Xinarianos G et al.. Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer.  Int J Cancer. 2009;  124(1) 81-87
    CrossrefPubMedGoogle Scholar
  • 5 Zaratiegui M, Irvine D V, Martienssen R A. Noncoding RNAs and gene silencing.  Cell. 2007;  128(4) 763-776
    CrossrefPubMedGoogle Scholar
  • 6 Dodge J E, Okano M, Dick F et al.. Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization.  J Biol Chem. 2005;  280(18) 17986-17991
    PubMedGoogle Scholar
  • 7 Hotchkiss R D. The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography.  J Biol Chem. 1948;  175(1) 315-332
    PubMedGoogle Scholar
  • 8 Griffith J S, Mahler H R. DNA ticketing theory of memory.  Nature. 1969;  223(5206) 580-582
    CrossrefPubMedGoogle Scholar
  • 9 Ratel D, Ravanat J L, Berger F, Wion D. N6-methyladenine: the other methylated base of DNA.  Bioessays. 2006;  28(3) 309-315
    CrossrefPubMedGoogle Scholar
  • 10 Sinsheimer R L. The action of pancreatic deoxyribonuclease. II. Isomeric dinucleotides.  J Biol Chem. 1955;  215(2) 579-583
    PubMedGoogle Scholar
  • 11 Woodcock D M, Crowther P J, Diver W P. The majority of methylated deoxycytidines in human DNA are not in the CpG dinucleotide.  Biochem Biophys Res Commun. 1987;  145(2) 888-894
    CrossrefPubMedGoogle Scholar
  • 12 Nyce J, Liu L, Jones P A. Variable effects of DNA-synthesis inhibitors upon DNA methylation in mammalian cells.  Nucleic Acids Res. 1986;  14(10) 4353-4367
    CrossrefPubMedGoogle Scholar
  • 13 Ramsahoye B H, Biniszkiewicz D, Lyko F, Clark V, Bird A P, Jaenisch R. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a.  Proc Natl Acad Sci U S A. 2000;  97(10) 5237-5242
    CrossrefPubMedGoogle Scholar
  • 14 Naveh-Many T, Cedar H. Active gene sequences are undermethylated.  Proc Natl Acad Sci U S A. 1981;  78(7) 4246-4250
    CrossrefPubMedGoogle Scholar
  • 15 Waechter D E, Baserga R. Effect of methylation on expression of microinjected genes.  Proc Natl Acad Sci U S A. 1982;  79(4) 1106-1110
    CrossrefPubMedGoogle Scholar
  • 16 Watt F, Molloy P L. Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter.  Genes Dev. 1988;  2(9) 1136-1143
    CrossrefPubMedGoogle Scholar
  • 17 Boyes J, Bird A. DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein.  Cell. 1991;  64(6) 1123-1134
    CrossrefPubMedGoogle Scholar
  • 18 Hendrich B, Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins.  Mol Cell Biol. 1998;  18(11) 6538-6547
    PubMedGoogle Scholar
  • 19 Jones P L, Veenstra G J, Wade P A et al.. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.  Nat Genet. 1998;  19(2) 187-191
    CrossrefPubMedGoogle Scholar
  • 20 Nan X, Ng H H, Johnson C A et al.. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.  Nature. 1998;  393(6683) 386-389
    CrossrefPubMedGoogle Scholar
  • 21 Leonhardt H, Page A W, Weier H U, Bestor T H. A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei.  Cell. 1992;  71(5) 865-873
    CrossrefPubMedGoogle Scholar
  • 22 Smith S S, Kaplan B E, Sowers L C, Newman E M. Mechanism of human methyl-directed DNA methyltransferase and the fidelity of cytosine methylation.  Proc Natl Acad Sci U S A. 1992;  89(10) 4744-4748
    PubMedGoogle Scholar
  • 23 Bestor T, Laudano A, Mattaliano R, Ingram V. Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases.  J Mol Biol. 1988;  203(4) 971-983
    CrossrefPubMedGoogle Scholar
  • 24 Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases.  Nat Genet. 1998;  19(3) 219-220
    CrossrefPubMedGoogle Scholar
  • 25 Okano M, Bell D W, Haber D A, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.  Cell. 1999;  99(3) 247-257
    CrossrefPubMedGoogle Scholar
  • 26 Kaneda M, Okano M, Hata K et al.. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting.  Nature. 2004;  429(6994) 900-903
    CrossrefPubMedGoogle Scholar
  • 27 Klose R J, Bird A P. Genomic DNA methylation: the mark and its mediators.  Trends Biochem Sci. 2006;  31(2) 89-97
    CrossrefPubMedGoogle Scholar
  • 28 Perche P Y, Robert-Nicoud M, Khochbin S, Vourc'h C. Nucleosome differentiation: role of histone H2A variants [in French].  Med Sci (Paris). 2003;  19(11) 1137-1145
    PubMedGoogle Scholar
  • 29 Redon C, Pilch D, Rogakou E, Sedelnikova O, Newrock K, Bonner W. Histone H2A variants H2AX and H2AZ.  Curr Opin Genet Dev. 2002;  12(2) 162-169
    CrossrefPubMedGoogle Scholar
  • 30 Hake S B, Allis C D. Histone H3 variants and their potential role in indexing mammalian genomes: the “H3 barcode hypothesis”.  Proc Natl Acad Sci U S A. 2006;  103(17) 6428-6435
    CrossrefPubMedGoogle Scholar
  • 31 Phillips D M, Johns E W. A fractionation of the histones of group F2a from calf thymus.  Biochem J. 1965;  94 127-130
    PubMedGoogle Scholar
  • 32 Kornberg R D. Chromatin structure: a repeating unit of histones and DNA.  Science. 1974;  184(139) 868-871
    CrossrefPubMedGoogle Scholar
  • 33 Kouzarides T. Chromatin modifications and their function.  Cell. 2007;  128(4) 693-705
    CrossrefPubMedGoogle Scholar
  • 34 Marmorstein R, Trievel R C. Histone modifying enzymes: structures, mechanisms, and specificities.  Biochim Biophys Acta. 2009;  1789(1) 58-68
    PubMedGoogle Scholar
  • 35 Strahl B D, Allis C D. The language of covalent histone modifications.  Nature. 2000;  403(6765) 41-45
    CrossrefPubMedGoogle Scholar
  • 36 Pogo B G, Allfrey V G, Mirsky A E. RNA synthesis and histone acetylation during the course of gene activation in lymphocytes.  Proc Natl Acad Sci U S A. 1966;  55(4) 805-812
    CrossrefPubMedGoogle Scholar
  • 37 Allfrey V G, Faulkner R, Mirsky A E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis.  Proc Natl Acad Sci U S A. 1964;  51 786-794
    CrossrefPubMedGoogle Scholar
  • 38 Sealy L, Chalkley R. DNA associated with hyperacetylated histone is preferentially digested by DNase I.  Nucleic Acids Res. 1978;  5(6) 1863-1876
    CrossrefPubMedGoogle Scholar
  • 39 Hong L, Schroth G P, Matthews H R, Yau P, Bradbury E M. Studies of the DNA binding properties of histone H4 amino terminus. Thermal denaturation studies reveal that acetylation markedly reduces the binding constant of the H4 “tail” to DNA.  J Biol Chem. 1993;  268(1) 305-314
    PubMedGoogle Scholar
  • 40 Norton V G, Imai B S, Yau P, Bradbury E M. Histone acetylation reduces nucleosome core particle linking number change.  Cell. 1989;  57(3) 449-457
    CrossrefPubMedGoogle Scholar
  • 41 Sims III R J, Nishioka K, Reinberg D. Histone lysine methylation: a signature for chromatin function.  Trends Genet. 2003;  19(11) 629-639
    CrossrefPubMedGoogle Scholar
  • 42 Parra M A, Wyrick J J. Regulation of gene transcription by the histone H2A N-terminal domain.  Mol Cell Biol. 2007;  27(21) 7641-7648
    CrossrefPubMedGoogle Scholar
  • 43 Parra M A, Kerr D, Fahy D, Pouchnik D J, Wyrick J J. Deciphering the roles of the histone H2B N-terminal domain in genome-wide transcription.  Mol Cell Biol. 2006;  26(10) 3842-3852
    CrossrefPubMedGoogle Scholar
  • 44 Weinberg M S, Villeneuve L M, Ehsani A et al.. The antisense strand of small interfering RNAs directs histone methylation and transcriptional gene silencing in human cells.  RNA. 2006;  12(2) 256-262
    PubMedGoogle Scholar
  • 45 Han J, Kim D, Morris K V. Promoter-associated RNA is required for RNA-directed transcriptional gene silencing in human cells.  Proc Natl Acad Sci U S A. 2007;  104(30) 12422-12427
    CrossrefPubMedGoogle Scholar
  • 46 Kim D H, Villeneuve L M, Morris K V, Rossi J J. Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells.  Nat Struct Mol Biol. 2006;  13(9) 793-797
    CrossrefPubMedGoogle Scholar
  • 47 Köhler C, Villar C B. Programming of gene expression by Polycomb group proteins.  Trends Cell Biol. 2008;  18(5) 236-243
    CrossrefPubMedGoogle Scholar
  • 48 Tagami H, Ray-Gallet D, Almouzni G, Nakatani Y. Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis.  Cell. 2004;  116(1) 51-61
    CrossrefPubMedGoogle Scholar
  • 49 Henikoff S, Furuyama T, Ahmad K. Histone variants, nucleosome assembly and epigenetic inheritance.  Trends Genet. 2004;  20(7) 320-326
    CrossrefPubMedGoogle Scholar
  • 50 Payer B, Lee J T. X chromosome dosage compensation: how mammals keep the balance.  Annu Rev Genet. 2008;  42 733-772
    CrossrefPubMedGoogle Scholar
  • 51 Huynh K D, Lee J T. X-chromosome inactivation: a hypothesis linking ontogeny and phylogeny.  Nat Rev Genet. 2005;  6(5) 410-418
    CrossrefPubMedGoogle Scholar
  • 52 Adler D A, Rugarli E I, Lingenfelter P A et al.. Evidence of evolutionary up-regulation of the single active X chromosome in mammals based on Clc4 expression levels in Mus spretus and Mus musculus.  Proc Natl Acad Sci U S A. 1997;  94(17) 9244-9248
    PubMedGoogle Scholar
  • 53 Lyon M F. Gene action in the X-chromosome of the mouse (Mus musculus L.)  Nature. 1961;  190 372-373
    CrossrefPubMedGoogle Scholar
  • 54 Sharman G B. Late DNA replication in the paternally derived X chromosome of female kangaroos.  Nature. 1971;  230(5291) 231-232
    CrossrefPubMedGoogle Scholar
  • 55 Cooper D W, VandeBerg J L, Sharman G B, Poole W E. Phosphoglycerate kinase polymorphism in kangaroos provides further evidence for paternal X inactivation.  Nat New Biol. 1971;  230(13) 155-157
    PubMedGoogle Scholar
  • 56 Huynh K D, Lee J T. Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos.  Nature. 2003;  426(6968) 857-862
    CrossrefPubMedGoogle Scholar
  • 57 Takagi N, Sasaki M. Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse.  Nature. 1975;  256(5519) 640-642
    PubMedGoogle Scholar
  • 58 Sado T, Fenner M H, Tan S S, Tam P, Shioda T, Li E. X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation.  Dev Biol. 2000;  225(2) 294-303
    CrossrefPubMedGoogle Scholar
  • 59 Wang J, Mager J, Chen Y et al.. Imprinted X inactivation maintained by a mouse Polycomb group gene.  Nat Genet. 2001;  28(4) 371-375
    PubMedGoogle Scholar
  • 60 Heard E, Disteche C M. Dosage compensation in mammals: fine-tuning the expression of the X chromosome.  Genes Dev. 2006;  20(14) 1848-1867
    CrossrefPubMedGoogle Scholar
  • 61 Lifschytz E, Lindsley D L. The role of X-chromosome inactivation during spermatogenesis (Drosophila-allocycly-chromosome evolution-male sterility-dosage compensation).  Proc Natl Acad Sci U S A. 1972;  69(1) 182-186
    CrossrefPubMedGoogle Scholar
  • 62 Okamoto I, Arnaud D, Le Baccon P et al.. Evidence for de novo imprinted X-chromosome inactivation independent of meiotic inactivation in mice.  Nature. 2005;  438(7066) 369-373
    CrossrefPubMedGoogle Scholar
  • 63 van der Heijden G W, Dieker J W, Derijck A A et al.. Asymmetry in histone H3 variants and lysine methylation between paternal and maternal chromatin of the early mouse zygote.  Mech Dev. 2005;  122(9) 1008-1022
    CrossrefPubMedGoogle Scholar
  • 64 Tada T, Obata Y, Tada M et al.. Imprint switching for non-random X-chromosome inactivation during mouse oocyte growth.  Development. 2000;  127(14) 3101-3105
    PubMedGoogle Scholar
  • 65 Norris D P, Patel D, Kay G F et al.. Evidence that random and imprinted Xist expression is controlled by preemptive methylation.  Cell. 1994;  77(1) 41-51
    CrossrefPubMedGoogle Scholar
  • 66 Surani M A, Barton S C, Norris M L. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis.  Nature. 1984;  308(5959) 548-550
    CrossrefPubMedGoogle Scholar
  • 67 McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes.  Cell. 1984;  37(1) 179-183
    CrossrefPubMedGoogle Scholar
  • 68 Bartolomei M S, Zemel S, Tilghman S M. Parental imprinting of the mouse H19 gene.  Nature. 1991;  351(6322) 153-155
    CrossrefPubMedGoogle Scholar
  • 69 Barlow D P, Stöger R, Herrmann B G, Saito K, Schweifer N. The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus.  Nature. 1991;  349(6304) 84-87
    CrossrefPubMedGoogle Scholar
  • 70 DeChiara T M, Robertson E J, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene.  Cell. 1991;  64(4) 849-859
    CrossrefPubMedGoogle Scholar
  • 71 Wilkins J F, Haig D. What good is genomic imprinting: the function of parent-specific gene expression.  Nat Rev Genet. 2003;  4(5) 359-368
    CrossrefPubMedGoogle Scholar
  • 72 Spahn L, Barlow D P. An ICE pattern crystallizes.  Nat Genet. 2003;  35(1) 11-12
    PubMedGoogle Scholar
  • 73 Obata Y, Kaneko-Ishino T, Koide T et al.. Disruption of primary imprinting during oocyte growth leads to the modified expression of imprinted genes during embryogenesis.  Development. 1998;  125(8) 1553-1560
    PubMedGoogle Scholar
  • 74 Davis T L, Yang G J, McCarrey J R, Bartolomei M S. The H19 methylation imprint is erased and re-established differentially on the parental alleles during male germ cell development.  Hum Mol Genet. 2000;  9(19) 2885-2894
    CrossrefPubMedGoogle Scholar
  • 75 Ueda T, Abe K, Miura A et al.. The paternal methylation imprint of the mouse H19 locus is acquired in the gonocyte stage during foetal testis development.  Genes Cells. 2000;  5(8) 649-659
    CrossrefPubMedGoogle Scholar
  • 76 Li J Y, Lees-Murdock D J, Xu G L, Walsh C P. Timing of establishment of paternal methylation imprints in the mouse.  Genomics. 2004;  84(6) 952-960
    CrossrefPubMedGoogle Scholar
  • 77 Lucifero D, Mann M R, Bartolomei M S, Trasler J M. Gene-specific timing and epigenetic memory in oocyte imprinting.  Hum Mol Genet. 2004;  13(8) 839-849
    CrossrefPubMedGoogle Scholar
  • 78 Hiura H, Obata Y, Komiyama J, Shirai M, Kono T. Oocyte growth-dependent progression of maternal imprinting in mice.  Genes Cells. 2006;  11(4) 353-361
    CrossrefPubMedGoogle Scholar
  • 79 Lee J T. Molecular links between X-inactivation and autosomal imprinting: X-inactivation as a driving force for the evolution of imprinting?.  Curr Biol. 2003;  13(6) R242-R254
    CrossrefPubMedGoogle Scholar
  • 80 Dean W, Santos F, Reik W. Epigenetic reprogramming in early mammalian development and following somatic nuclear transfer.  Semin Cell Dev Biol. 2003;  14(1) 93-100
    CrossrefPubMedGoogle Scholar
  • 81 Nakamura T, Arai Y, Umehara H et al.. PGC7/Stella protects against DNA demethylation in early embryogenesis.  Nat Cell Biol. 2007;  9(1) 64-71
    CrossrefPubMedGoogle Scholar
  • 82 Morgan H D, Sutherland H G, Martin D I, Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse.  Nat Genet. 1999;  23(3) 314-318
    CrossrefPubMedGoogle Scholar
  • 83 Lane N, Dean W, Erhardt S et al.. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse.  Genesis. 2003;  35(2) 88-93
    CrossrefPubMedGoogle Scholar
  • 84 Maher E R, Afnan M, Barratt C L. Epigenetic risks related to assisted reproductive technologies: epigenetics, imprinting, ART and icebergs?.  Hum Reprod. 2003;  18(12) 2508-2511
    CrossrefPubMedGoogle Scholar
  • 85 Barker D J. Intrauterine programming of coronary heart disease and stroke.  Acta Paediatr Suppl. 1997;  423 178-182 discussion 183
    PubMedGoogle Scholar
  • 86 Doherty A S, Mann M R, Tremblay K D, Bartolomei M S, Schultz R M. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo.  Biol Reprod. 2000;  62(6) 1526-1535
    CrossrefPubMedGoogle Scholar
  • 87 Li T, Vu T H, Ulaner G A et al.. IVF results in de novo DNA methylation and histone methylation at an Igf2-H19 imprinting epigenetic switch.  Mol Hum Reprod. 2005;  11(9) 631-640
    CrossrefPubMedGoogle Scholar
  • 88 Khosla S, Dean W, Brown D, Reik W, Feil R. Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes.  Biol Reprod. 2001;  64(3) 918-926
    CrossrefPubMedGoogle Scholar
  • 89 Khosla S, Dean W, Reik W, Feil R. Culture of preimplantation embryos and its long-term effects on gene expression and phenotype.  Hum Reprod Update. 2001;  7(4) 419-427
    CrossrefPubMedGoogle Scholar
  • 90 Wu Q, Ohsako S, Ishimura R, Suzuki J S, Tohyama C. Exposure of mouse preimplantation embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the methylation status of imprinted genes H19 and Igf2.  Biol Reprod. 2004;  70(6) 1790-1797
    CrossrefPubMedGoogle Scholar
  • 91 Shao W J, Tao L Y, Xie J Y, Gao C, Hu J H, Zhao R Q. Exposure of preimplantation embryos to insulin alters expression of imprinted genes.  Comp Med. 2007;  57(5) 482-486
    PubMedGoogle Scholar

Carol A BrennerPh.D. 

Departments of Obstetrics & Gynecology and Physiology, CS Mott Center for Human Growth and Development, Wayne State University, School of Medicine

275 E. Hancock St., Detroit, MI 48201

Email: cbrenner@med.wayne.edu

      >