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Epigenetics of sex determination in mammals

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Reproductive Medicine and Biology

Abstract

Epigenetics is the study of changes in gene function that cannot be explained by changes in DNA sequence. A mammalian body contains more than two hundred types of cells. Since all of them are derived from a single fertilized egg, their genotypes are identical. However, the gene expression patterns are different between the cell types, indicating that each cell type has unique own “epigenotype”. Epigenetic gene regulation mechanisms essentially contribute to various processes of mammalian development. The essence of epigenetic regulation is the structural change of chromatin to modulate gene activity in a spatiotemporal manner. DNA methylation and histone modifications are the major epigenetic mechanisms. Sex determination is the process for gender establishment. There are two types of sex-determining mechanisms in animals, environmental sex determination (ESD) and genotypic sex determination (GSD). Recent studies have provided some evidence that epigenetic mechanisms play indispensable roles in ESD and GSD. Some fishes undergo ESD, in which DNA methylation is essentially involved. GSD is employed in therian mammals, where Sry (sex-determining region on the Y chromosome) triggers testis differentiation from undifferentiated gonads. Sry expression is tightly regulated in a spatiotemporal manner. A recent study demonstrated that histone modification is involved in Sry regulation. In this review, we discuss the role of epigenetic mechanisms for sex determination in mammals and other vertebrates.

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References

  1. Russo VEA, Martienssen RA, Riggs AD. Epigenetic mechanisms of gene regulation. Plainview: Cold Spring Harbor Laboratory Press; 1996.

    Google Scholar 

  2. Gilbert SF, Epel D. Ecological developmental biology:integrating epigenetics, medicine, and evolution. Sunderland: Sinauer Associates; 2009.

    Google Scholar 

  3. Wakimoto BT. Beyond the nucleosome: epigenetic aspects of position-effect variegation in Drosophila. Cell. 1998;93:321–4.

    Article  CAS  PubMed  Google Scholar 

  4. Brock HW, Fisher CL. Maintenance of gene expression patterns. Dev Dyn. 2005;232:633–55.

    Article  CAS  PubMed  Google Scholar 

  5. Waddington CH. The epigenotype. 1942. Int J Epidemiol. 2012;41:10–3.

    Article  CAS  PubMed  Google Scholar 

  6. Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998;19:187–91.

    Article  CAS  PubMed  Google Scholar 

  7. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998;393:386–9.

    Article  CAS  PubMed  Google Scholar 

  8. Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH. Suv39 h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol. 2003;13:1192–200.

    Article  CAS  PubMed  Google Scholar 

  9. Gibbons RJ, McDowell TL, Raman S, O’Rourke DM, Garrick D, Ayyub H, Higgs DR. Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nat Genet. 2000;24:368–71.

    Article  CAS  PubMed  Google Scholar 

  10. Dennis K, Fan T, Geiman T, Yan Q, Muegge K. Lsh, a member of the SNF2 family, is required for genome-wide methylation. Genes Dev. 2001;15:2940–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sado T, Brockdorff N. Advances in understanding chromosome silencing by the long non-coding RNA Xist. Philos Trans R Soc Lon Ser B. Biol Sci. 2013;368:20110325.

    Article  Google Scholar 

  12. Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007;447:425–32.

    Article  CAS  PubMed  Google Scholar 

  13. Turner BM. Epigenetic responses to environmental change and their evolutionary implications. Philos Trans R Soc Lond B Biol Sci. 2009;364:3403–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005;102:10604–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Paszkowski J, Grossniklaus U. Selected aspects of transgenerational epigenetic inheritance and resetting in plants. Curr Opin Plant Biol. 2011;14:195–203.

    Article  CAS  PubMed  Google Scholar 

  16. Morgan HD, Sutherland HG, Martin DI, Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse. Nat Genet. 1999;23:314–8.

    Article  CAS  PubMed  Google Scholar 

  17. Duhl DM, Vrieling H, Miller KA, Wolff GL, Barsh GS. Neomorphic agouti mutations in obese yellow mice. Nat Genet. 1994;8:59–65.

    Article  CAS  PubMed  Google Scholar 

  18. Rakyan VK, Chong S, Champ ME, Cuthbert PC, Morgan HD, Luu KV, Whitelaw E. Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci USA. 2003;100:2538–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Daxinger L, Whitelaw E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat Rev Genet. 2012;13:153–62.

    Article  CAS  PubMed  Google Scholar 

  20. Valenzuela N, Lance V. Temperature-dependent sex determination in vertebrates. Washington DC: Smithsonian Books; 2004.

    Google Scholar 

  21. Penman DJ, Piferrer F. Fish Gonadogenesis. Part I: genetic and environmental mechanisms of sex determination. Rev Fish Sci. 2008;16:16–34.

    Article  CAS  Google Scholar 

  22. Munger SC, Capel B. Sex and the circuitry: progress toward a systems-level understanding of vertebrate sex determination. Wiley Interdiscip Rev Syst Biol Med. 2012;4:401–12.

    Article  CAS  PubMed  Google Scholar 

  23. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247–57.

    Article  CAS  PubMed  Google Scholar 

  24. Hermann A, Gowher H, Jeltsch A. Biochemistry and biology of mammalian DNA methyltransferases. Cell Mol Life Sci. 2004;61:2571–87.

    Article  CAS  PubMed  Google Scholar 

  25. Strogantsev R, Ferguson-Smith AC. Proteins involved in establishment and maintenance of imprinted methylation marks. Brief Funct Genom. 2012;11:227–39.

    Article  CAS  Google Scholar 

  26. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466:1129–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wu H, Zhang Y. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev. 2011;25:2436–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yamaguchi S, Shen L, Liu Y, Sendler D, Zhang Y. Role of Tet1 in erasure of genomic imprinting. Nature. 2013;504:460–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lance VA. Is regulation of aromatase expression in reptiles the key to understanding temperature-dependent sex determination? J Exp Zool A Ecol Genet Physiol. 2009;311:314–22.

    Article  PubMed  Google Scholar 

  31. Piferrer F, Blazquez M, Navarro L, Gonzalez A. Genetic, endocrine, and environmental components of sex determination and differentiation in the European sea bass (Dicentrarchus labrax L.). Gen Comp Endocrinol. 2005;142:102–10.

    Article  CAS  PubMed  Google Scholar 

  32. Vandeputte M, Dupont-Nivet M, Chavanne H, Chatain B. A polygenic hypothesis for sex determination in the European sea bass Dicentrarchus labrax. Genetics. 2007;176:1049–57.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Navarro-Martin L, Vinas J, Ribas L, Diaz N, Gutierrez A, Di Croce L, Piferrer F. DNA methylation of the gonadal aromatase (cyp19a) promoter is involved in temperature-dependent sex ratio shifts in the European sea bass. PLoS Genet. 2011;7:e1002447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R, Goodfellow PN. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990;346:240–4.

    Article  CAS  PubMed  Google Scholar 

  35. Gubbay J, Collignon J, Koopman P, Capel B, Economou A, Munsterberg A, Vivian N, Goodfellow P, Lovell-Badge R. A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature. 1990;346:245–50.

    Article  CAS  PubMed  Google Scholar 

  36. Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R. Male development of chromosomally female mice transgenic for Sry. Nature. 1991;351:117–21.

    Article  CAS  PubMed  Google Scholar 

  37. Harley VR, Goodfellow PN. The biochemical role of SRY in sex determination. Mol Reprod Dev. 1994;39:184–93.

    Article  CAS  PubMed  Google Scholar 

  38. Kashimada K, Koopman P. Sry: the master switch in mammalian sex determination. Development. 2010;137:3921–30.

    Article  CAS  PubMed  Google Scholar 

  39. Koopman P, Munsterberg A, Capel B, Vivian N, Lovell-Badge R. Expression of a candidate sex-determining gene during mouse testis differentiation. Nature. 1990;348:450–2.

    Article  CAS  PubMed  Google Scholar 

  40. Hacker A, Capel B, Goodfellow P, Lovell-Badge R. Expression of Sry, the mouse sex determining gene. Development. 1995;121:1603–14.

    CAS  PubMed  Google Scholar 

  41. Jeske YW, Bowles J, Greenfield A, Koopman P. Expression of a linear Sry transcript in the mouse genital ridge. Nat Genet. 1995;10:480–2.

    Article  CAS  PubMed  Google Scholar 

  42. Bullejos M, Koopman P. Delayed Sry and Sox9 expression in developing mouse gonads underlies B6-Y(DOM) sex reversal. Dev Biol. 2005;278:473–81.

    Article  CAS  PubMed  Google Scholar 

  43. Wilhelm D, Martinson F, Bradford S, Wilson MJ, Combes AN, Beverdam A, Bowles J, Mizusaki H, Koopman P. Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determination. Dev Biol. 2005;287:111–24.

    Article  CAS  PubMed  Google Scholar 

  44. Nishino K, Hattori N, Tanaka S, Shiota K. DNA methylation-mediated control of Sry gene expression in mouse gonadal development. J Biol Chem. 2004;279:22306–13.

    Article  CAS  PubMed  Google Scholar 

  45. Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Laurent L, Wong E, Li G, Huynh T, Tsirigos A, Ong CT, Low HM, Kin Sung KW, Rigoutsos I, Loring J, Wei CL. Dynamic changes in the human methylome during differentiation. Genome Res. 2010;20:320–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. 2011;471:68–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Scholer A, van Nimwegen E, Wirbelauer C, Oakeley EJ, Gaidatzis D, Tiwari VK, Schubeler D. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011;480:490–5.

    CAS  PubMed  Google Scholar 

  49. Xie W, Barr CL, Kim A, Yue F, Lee AY, Eubanks J, Dempster EL, Ren B. Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell. 2012;148:816–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nishino K, Hattori N, Sato S, Arai Y, Tanaka S, Nagy A, Shiota K. Non-CpG methylation occurs in the regulatory region of the Sry gene. J Reprod Dev. 2011;57:586–93.

    Article  CAS  PubMed  Google Scholar 

  51. Meehan RR, Lewis JD, Bird AP. Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. Nucleic Acids Res. 1992;20:5085–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Guo JU, Su Y, Shin JH, Shin J, Li H, Xie B, Zhong C, Hu S, Le T, Fan G, Zhu H, Chang Q, Gao Y, Ming GL, Song H. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci. 2014;17:215–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nan X, Meehan RR, Bird A. Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res. 1993;21:4886–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hollander MC, Fornace AJ Jr. Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a. Oncogene. 2002;21:6228–33.

    Article  CAS  PubMed  Google Scholar 

  55. Liebermann DA, Tront JS, Sha X, Mukherjee K, Mohamed-Hadley A, Hoffman B. Gadd45 stress sensors in malignancy and leukemia. Crit Rev Oncog. 2011;16:129–40.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Barreto G, Schafer A, Marhold J, Stach D, Swaminathan SK, Handa V, Doderlein G, Maltry N, Wu W, Lyko F, Niehrs C. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature. 2007;445:671–5.

    Article  CAS  PubMed  Google Scholar 

  57. Warr N, Carre GA, Siggers P, Faleato JV, Brixey R, Pope M, Bogani D, Childers M, Wells S, Scudamore CL, Tedesco M, del Barco Barrantes I, Nebreda AR, Trainor PA, Greenfield A. Gadd45γ and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression. Dev Cell. 2012;23:1020–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gierl MS, Gruhn WH, von Seggern A, Maltry N, Niehrs C. GADD45G functions in male sex determination by promoting p38 signaling and Sry expression. Dev Cell. 2012;23:1032–42.

    Article  CAS  PubMed  Google Scholar 

  59. Tevosian SG, Albrecht KH, Crispino JD, Fujiwara Y, Eicher EM, Orkin SH. Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2. Development. 2002;129:4627–34.

    CAS  PubMed  Google Scholar 

  60. Klose RJ, Zhang Y. Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol. 2007;8:307–18.

    Article  CAS  PubMed  Google Scholar 

  61. Kooistra SM, Helin K. Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol. 2012;13:297–311.

    CAS  PubMed  Google Scholar 

  62. Nakayama J, Rice JC, Strahl BD, Allis CD, Grewal SI. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science. 2001;292:110–3.

    Article  CAS  PubMed  Google Scholar 

  63. Peters AH, O’Carroll D, Scherthan H, Mechtler K, Sauer S, Schofer C, Weipoltshammer K, Pagani M, Lachner M, Kohlmaier A, Opravil S, Doyle M, Sibilia M, Jenuwein T. Loss of the Suv39 h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell. 2001;107:323–37.

    Article  CAS  PubMed  Google Scholar 

  64. Tachibana M, Nozaki M, Takeda N, Shinkai Y. Functional dynamics of H3K9 methylation during meiotic prophase progression. EMBO J. 2007;26:3346–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J, Zhang Y. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell. 2006;125:483–95.

    Article  CAS  PubMed  Google Scholar 

  66. Tateishi K, Okada Y, Kallin EM, Zhang Y. Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature. 2009;458:757–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Inagaki T, Tachibana M, Magoori K, Kudo H, Tanaka T, Okamura M, Naito M, Kodama T, Shinkai Y, Sakai J. Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice. Genes Cells. 2009;14:991–1001.

    Article  CAS  PubMed  Google Scholar 

  68. Kuroki S, Matoba S, Akiyoshi M, Matsumura Y, Miyachi H, Mise N, Abe K, Ogura A, Wilhelm D, Koopman P, Nozaki M, Kanai Y, Shinkai Y, Tachibana M. Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Science. 2013;341:1106–9.

    Article  CAS  PubMed  Google Scholar 

  69. Kidokoro T, Matoba S, Hiramatsu R, Fujisawa M, Kanai-Azuma M, Taya C, Kurohmaru M, Kawakami H, Hayashi Y, Kanai Y, Yonekawa H. Influence on spatiotemporal patterns of a male-specific Sox9 activation by ectopic Sry expression during early phases of testis differentiation in mice. Dev Biol. 2005;278:511–25.

    Article  CAS  PubMed  Google Scholar 

  70. Lewis EB. A gene complex controlling segmentation in Drosophila. Nature. 1978;276:565–70.

    Article  CAS  PubMed  Google Scholar 

  71. Simon JA, Kingston RE. Occupying chromatin: polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put. Mol Cell. 2013;49:808–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Katoh-Fukui Y, Tsuchiya R, Shiroishi T, Nakahara Y, Hashimoto N, Noguchi K, Higashinakagawa T. Male-to-female sex reversal in M33 mutant mice. Nature. 1998;393:688–92.

    Article  CAS  PubMed  Google Scholar 

  73. Katoh-Fukui Y, Owaki A, Toyama Y, Kusaka M, Shinohara Y, Maekawa M, Toshimori K, Morohashi K. Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression. Blood. 2005;106:1612–20.

    Article  CAS  PubMed  Google Scholar 

  74. Katoh-Fukui Y, Miyabayashi K, Komatsu T, Owaki A, Baba T, Shima Y, Kidokoro T, Kanai Y, Schedl A, Wilhelm D, Koopman P, Okuno Y, Morohashi K. Cbx2, a polycomb group gene, is required for Sry gene expression in mice. Endocrinology. 2012;153:913–24.

    Article  CAS  PubMed  Google Scholar 

  75. Ku M, Koche RP, Rheinbay E, Mendenhall EM, Endoh M, Mikkelsen TS, Presser A, Nusbaum C, Xie X, Chi AS, Adli M, Kasif S, Ptaszek LM, Cowan CA, Lander ES, Koseki H, Bernstein BE. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet. 2008;4:e1000242.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jaenisch R. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006;441:349–53.

    Article  CAS  PubMed  Google Scholar 

  77. Shao C, Li Q, Chen S, Zhang P, Lian J, Hu Q, Sun B, Jin L, Liu S, Wang Z, Zhao H, Jin Z, Liang Z, Li Y, Zheng Q, Zhang Y, Wang J, Zhang G. Epigenetic modification and inheritance in sexual reversal of fish. Genome Res. 2014;24:604–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gluckman PD, Hanson MA, Buklijas T, Low FM, Beedle AS. Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol. 2009;5:401–8.

    Article  CAS  PubMed  Google Scholar 

  79. Rosenfeld CS. Animal models to study environmental epigenetics. Biol Reprod. 2010;82:473–88.

    Article  CAS  PubMed  Google Scholar 

  80. Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect. 2006;114:567–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci USA. 2007;104:13056–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kaminen-Ahola N, Ahola A, Maga M, Mallitt KA, Fahey P, Cox TC, Whitelaw E, Chong S. Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model. PLoS Genet. 2010;6:e1000811.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Fujimoto Y, Tanaka SS, Yamaguchi YL, Kobayashi H, Kuroki S, Tachibana M, Shinomura M, Kanai Y, Morohashi K, Kawakami K, Nishinakamura R. Homeoproteins Six1 and Six4 regulate male sex determination and mouse gonadal development. Dev Cell. 2013;26:416–30.

    Article  CAS  PubMed  Google Scholar 

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Tachibana, M. Epigenetics of sex determination in mammals. Reprod Med Biol 15, 59–67 (2016). https://doi.org/10.1007/s12522-015-0223-7

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