@2024 Afarand., IRAN
ISSN: 2251-8215 Sarem Journal of Reproductive Medicine 2018;2(4):
ISSN: 2251-8215 Sarem Journal of Reproductive Medicine 2018;2(4):
Role of Epigenetics in Male Infertility
ARTICLE INFO
Article Type
Systematic ReviewAuthors
Akhtarkhavari T. (1)Behjati F. (*)
(*) *“Sarem Fertility & Infertility Research Center (SAFIR)” and “Sarem Cell Research Center (SCRC), Sarem Women’s Hospital" and “Genetics Research Center, University of Social Welfare and Rehabilitation Sciences”, Tehran, Iran
(1) Sarem Cell Research Center (SCRC), Sarem Women’s Hospital, Tehran, Iran
Correspondence
Address: Sarem Women’s Hospital, Basij Square, Phase 3, Ekbatan Town, Tehran, Iran. Postal Code: 1396956111Phone: +98 (21) 44670888
Fax: +98 (21) 44670432
fbehjati@gmail.com
Article History
Received: April 3, 2017Accepted: October 20, 2017
ePublished: November 15, 2017
ABSTRACT
Instrument & Methods
Male infertility is a complex medical condition, within which epigenetic factors play an important role. The present review study was conducted to collect epigenetic changes in infertile men. Therefore, more than 50 articles published in the PubMed database were reviewed. All articles published until April 2016 containing the keywords epigenetics, epimutation, and epidrug with the word infertility were reviewed.
Conclusion The recent studies have revealed the effects of several epigenetic factors on infertility in men, including histone modification, defects in chromatin-modifying complexes, and methylation modification in promoters of various genes. At present, the available treatments do not account for all infertile men, and this is especially important for idiopathic infertility. Regarding the epigenetic role in male infertility, recognizing epigenetic mechanisms enables us to develop new epidrugs that can be used in the treatment of infertility in near future.
Conclusion The recent studies have revealed the effects of several epigenetic factors on infertility in men, including histone modification, defects in chromatin-modifying complexes, and methylation modification in promoters of various genes. At present, the available treatments do not account for all infertile men, and this is especially important for idiopathic infertility. Regarding the epigenetic role in male infertility, recognizing epigenetic mechanisms enables us to develop new epidrugs that can be used in the treatment of infertility in near future.
CITATION LINKS
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[2]Gunes S, Arslan MA, Hekim GN, Asci R. The role of epigenetics in idiopathic male infertility. J Assist Reprod Genet. 2016;33(5):553-69.
[3]Rajender S, Avery K, Agarwal A. Epigenetics, spermatogenesis and male infertility. Mutat Res. 2011;727(3):62-71.
[4]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(3):247-57.
[5]Nimura K, Ishida C, Koriyama H, Hata K, Yamanaka S, Li E, et al. Dnmt3a2 targets endogenous Dnmt3L to ES cell chromatin and induces regional DNA methylation. Genes Cells. 2006;11(10):1225-37.
[6]Ait-Si-Ali S, Guasconi V, Fritsch L, Yahi H, Sekhri R, Naguibneva I, et al. A Suv39h-dependent mechanism for silencing S-phase genes in differentiating but not in cycling cells. Eur Mol Biol Organ J. 2004;23(3):605-15.
[7]Tachibana M, Nozaki M, Takeda N, Shinkai Y. Functional dynamics of H3K9 methylation during meiotic prophase progression. Eur Mol Biol Organ J. 2007;26(14):3346-59.
[8]Klenova EM, Morse HC, 3rd, Ohlsson R, Lobanenkov VV. The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer. Semin Cancer Biol. 2002;12(5):399-414.
[9]Loukinov DI, Pugacheva E, Vatolin S, Pack SD, Moon H, Chernukhin I, et al. BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc Natl Acad Sci U S A. 2002;99(10):6806-11.
[10]Rimoin DL, Pyeritz RE, Korf B. Emery and Rimoin's principles and practice of medical genetics. Amsterdam: Elsevier Science; 2013.
[11]Zamudio NM, Chong S, O'Bryan MK. Epigenetic regulation in male germ cells. Reproduction. 2008;136(2):131-46.
[12]Stuppia L, Franzago M, Ballerini P, Gatta V, Antonucci I. Epigenetics and male reproduction: The consequences of paternal lifestyle on fertility, embryo development, and children lifetime health. Clin Epigenetics. 2015;7:105-20.
[13]Oliva R. Protamines and male infertility. Hum Reprod Update. 2006;12(4):417-35.
[14]Oliva R, Bazett-Jones D, Mezquita C, Dixon GH. Factors affecting nucleosome disassembly by protamines in vitro. Histone hyperacetylation and chromatin structure, time dependence, and the size of the sperm nuclear proteins. J Biol Chem. 1987;262(35):17016-25.
[15]Oliva R, Dixon GH. Vertebrate protamine genes and the histone-to-protamine replacement reaction. Prog Nucleic Acid Res Mol Biol. 1991;40:25-94.
[16]Dada R, Kumar M, Jesudasan R, Fernández JL, Gosálvez J, Agarwal A. Epigenetics and its role in male infertility. J Assist Reprod Genet. 2012;29(3):213-23.
[17]Lambard S, Galeraud-Denis I, Martin G, Levy R, Chocat A, Carreau S. Analysis and significance of mRNA in human ejaculated sperm from normozoospermic donors: Relationship to sperm motility and capacitation. Mol Hum Reprod. 2004;10(7):535-41.
[18]Khazamipour N, Noruzinia M, Fatehmanesh P, Keyhanee M, Pujol P. MTHFR promoter hypermethylation in testicular biopsies of patients with non-obstructive azoospermia: The role of epigenetics in male infertility. Hum Reprod. 2009;24(9):2361-4.
[19]Wu W, Shen O, Qin Y, Niu X, Lu C, Xia Y, et al. Idiopathic male infertility is strongly associated with aberrant promoter methylation of methylenetetrahydrofolate reductase (MTHFR). PLoS One. 2010;5(11):e13884.
[20]Chan D, Cushnie DW, Neaga OR, Lawrance AK, Rozen R, Trasler JM. Strain-specific defects in testicular development and sperm epigenetic patterns in 5,10-methylenetetrahydrofolate reductase-deficient mice. Endocrinology. 2010;151(7):3363-73.
[21]Houshdaran S, Cortessis VK, Siegmund K, Yang A, Laird PW, Sokol RZ. Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm. PLoS One. 2007;2(12):e1289.
[22]Kumar R, Venkatesh S, Kumar M, Tanwar M, Shasmsi MB, Kumar R, et al. Oxidative stress and sperm mitochondrial DNA mutation in idiopathic oligoasthenozoospermic men. Indian J Biochem Biophys. 2009;46(2):172-7.
[23]Poplinski A, Tuttelmann F, Kanber D, Horsthemke B, Gromoll J. Idiopathic male infertility is strongly associated with aberrant methylation of MEST and IGF2/H19 ICR1. Int J Androl 2010;33(4):642-9.
[24]Hammoud SS, Purwar J, Pflueger C, Cairns BR, Carrell DT. Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility. Fertil Steril. 2010;94(5):1728-33.
[25]Kobayashi H, Sato A, Otsu E, Hiura H, Tomatsu C, Utsunomiya T, et al. Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients. Hum Mol Genet. 2007;16(21):2542-51.
[26]Li JY, Lees-Murdock DJ, Xu GL, Walsh CP. Timing of establishment of paternal methylation imprints in the mouse. Genomics. 2004;84(6):952-60.
[27]Baarends WM, Wassenaar E, van der Laan R, Hoogerbrugge J, Sleddens-Linkels E, Hoeijmakers JH, et al. Silencing of unpaired chromatin and histone H2A ubiquitination in mammalian meiosis. Mol Cell Biol. 2005;25(3):1041-53.
[28]Okada Y, Scott G, Ray MK, Mishina Y, Zhang Y. Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature. 2007;450(7166):119-23.
[29]Wu JY, Ribar TJ, Cummings DE, Burton KA, McKnight GS, Means AR. Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4. Nat Genet. 2000;25(4):448-52.
[30]Aoki VW, Emery BR, Liu L, Carrell DT. Protamine Levels vary between individual sperm cells of infertile human males and correlate with viability and DNA integrity. J Androl. 2006;27(6):890-8.
[31]Moghbelinejad S, Najafipour R, Hashjin AS. Comparison of Protamine 1 to Protamine 2 mRNA ratio and YBX2 gene mRNA content in testicular tissue of Fertile and Azoospermic Men. Int J Fertil Steril. 2015;9(3):338-45.
[32]Li C, Zheng L, Wang C, Zhou X. Absence of nerve growth factor and comparison of tyrosine kinase receptor A levels in mature spermatozoa from Oligoasthenozoospermic, Asthenozoospermic and Fertile men. Clin Chim Acta. 2010;411(19-20):1482-6.
[33]Guo X, Gui YT, Tang AF, Lu LH, Gao X, Cai ZM. Differential expression of VASA gene in ejaculated Spermatozoa from Normozoospermic men and patients with Oligozoospermia. Asian J Androl. 2007;9(3):339-44.
[34]Krawetz SA, Kruger A, Lalancette C, Tagett R, Anton E, Draghici S, et al. A survey of small RNAs in human sperm. Hum Reprod. 2011;26(12):3401-12.
[35]Papaioannou MD, Nef S. MicroRNAs in the testis: Building up male fertility. J Androl. 2010;31(1):26-33.
[36]Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259-69.
[37]Bjork JK, Sandqvist A, Elsing AN, Kotaja N, Sistonen L. The miR-18a member of Oncomir-1, targets heat shock transcription factor 2 in spermatogenesis. Development. 2010;137(19):3177-84.
[38]Barad O, Meiri E, Avniel A, Aharonov R, Barzilai A, Bentwich I, et al. MicroRNA expression detected by oligonucleotide microarrays: System establishment and expression profiling in human tissues. Genome Res. 2004;14(12):2486-94.
[39]Yu Z, Raabe T, Hecht NB. MicroRNA Mirn122a reduces expression of the Posttranscriptionally regulated germ cell transition protein 2 (Tnp2) messenger RNA (mRNA) by mRNA cleavage. Biol Reprod. 2005;73(3):427-33.
[40]Novotny GW, Sonne SB, Nielsen JE, Jonstrup SP, Hansen MA, Skakkebaek NE, et al. Translational repression of E2F1 mRNA in arcinoma in situ and normal testis correlates with expression of the miR-17-92 cluster. Cell Death Differ. 2007;14(4):879-82.
[41]Huang S, Li H, Ding X, Xiong C. Presence and characterization of cell-free seminal RNA in healthy individuals: Implications for noninvasive disease diagnosis and gene expression studies of the male reproductive system. Clin Chem. 2009;55(11):1967-76.
[42]Klattenhoff C, Theurkauf W. Biogenesis and germline functions of piRNAs. Development. 2008;135(1):3-9.
[43]Peters AH, O'Carroll D, Scherthan H, Mechtler K, Sauer S, Schofer C, et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell. 2001;107(3):323-37.
[44]Glaser S, Lubitz S, Loveland KL, Ohbo K, Robb L, Schwenk F, et al. The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis. Epigenetics Chromatin. 2009;2(1):5.
[45]Hayashi K, Yoshida K, Matsui Y. A histone H3 methyltransferase controls epigenetic events required for meiotic prophase. Nature. 2005;438(7066):374-8.
[46]Ciccone DN, Su H, Hevi S, Gay F, Lei H, Bajko J, et al. KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature. 2009;461(7262):415-8.
[47]An JY, Kim EA, Jiang Y, Zakrzewska A, Kim DE, Lee MJ, et al. UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination. Proc Natl Acad Sci USA. 2010;107(5):1912-7.
[48]Lu LY, Wu J, Ye L, Gavrilina GB, Saunders TL, Yu X. RNF8-dependent histone modifications regulate nucleosome removal during spermatogenesis. Dev cell. 2010;18(3):371-84.
[49]De La Fuente R, Baumann C, Fan T, Schmidtmann A, Dobrinski I, Muegge K. Lsh is required for meiotic chromosome synapsis and retrotransposon silencing in female germ cells. Nat Cell Biol. 2006;8(12):1448-54.
[50]Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, et al. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature. 2004;429(6994):900-3.
[51]Kato Y, Kaneda M, Hata K, Kumaki K, Hisano M, Kohara Y, et al. Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse. Hum Mol Genet. 2007;16(19):2272-80.
[52]Aravin AA, Sachidanandam R, Girard A, Fejes-Toth K, Hannon GJ. Developmentally regulated piRNA clusters implicate MILI in transposon control. Science. 2007;316(5825):744-7.
[53]Deng W, Lin H. MIVI, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Dev Cell. 2002;2(6):819-30.
[54]Carmell MA, Girard A, van de Kant HJ, Bourc'his D, Bestor TH, de Rooij DG, et al. MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev Cell. 2007;12(4):503-14.
[55]Shang E, Nickerson HD, Wen D, Wang X, Wolgemuth DJ. The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation. Development. 2007;134(19):3507-15.
[56]Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of adult disease: Strength of effects and biological basis. Int J Epidemiol. 2002;31(6):1235-9.
[2]Gunes S, Arslan MA, Hekim GN, Asci R. The role of epigenetics in idiopathic male infertility. J Assist Reprod Genet. 2016;33(5):553-69.
[3]Rajender S, Avery K, Agarwal A. Epigenetics, spermatogenesis and male infertility. Mutat Res. 2011;727(3):62-71.
[4]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(3):247-57.
[5]Nimura K, Ishida C, Koriyama H, Hata K, Yamanaka S, Li E, et al. Dnmt3a2 targets endogenous Dnmt3L to ES cell chromatin and induces regional DNA methylation. Genes Cells. 2006;11(10):1225-37.
[6]Ait-Si-Ali S, Guasconi V, Fritsch L, Yahi H, Sekhri R, Naguibneva I, et al. A Suv39h-dependent mechanism for silencing S-phase genes in differentiating but not in cycling cells. Eur Mol Biol Organ J. 2004;23(3):605-15.
[7]Tachibana M, Nozaki M, Takeda N, Shinkai Y. Functional dynamics of H3K9 methylation during meiotic prophase progression. Eur Mol Biol Organ J. 2007;26(14):3346-59.
[8]Klenova EM, Morse HC, 3rd, Ohlsson R, Lobanenkov VV. The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer. Semin Cancer Biol. 2002;12(5):399-414.
[9]Loukinov DI, Pugacheva E, Vatolin S, Pack SD, Moon H, Chernukhin I, et al. BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc Natl Acad Sci U S A. 2002;99(10):6806-11.
[10]Rimoin DL, Pyeritz RE, Korf B. Emery and Rimoin's principles and practice of medical genetics. Amsterdam: Elsevier Science; 2013.
[11]Zamudio NM, Chong S, O'Bryan MK. Epigenetic regulation in male germ cells. Reproduction. 2008;136(2):131-46.
[12]Stuppia L, Franzago M, Ballerini P, Gatta V, Antonucci I. Epigenetics and male reproduction: The consequences of paternal lifestyle on fertility, embryo development, and children lifetime health. Clin Epigenetics. 2015;7:105-20.
[13]Oliva R. Protamines and male infertility. Hum Reprod Update. 2006;12(4):417-35.
[14]Oliva R, Bazett-Jones D, Mezquita C, Dixon GH. Factors affecting nucleosome disassembly by protamines in vitro. Histone hyperacetylation and chromatin structure, time dependence, and the size of the sperm nuclear proteins. J Biol Chem. 1987;262(35):17016-25.
[15]Oliva R, Dixon GH. Vertebrate protamine genes and the histone-to-protamine replacement reaction. Prog Nucleic Acid Res Mol Biol. 1991;40:25-94.
[16]Dada R, Kumar M, Jesudasan R, Fernández JL, Gosálvez J, Agarwal A. Epigenetics and its role in male infertility. J Assist Reprod Genet. 2012;29(3):213-23.
[17]Lambard S, Galeraud-Denis I, Martin G, Levy R, Chocat A, Carreau S. Analysis and significance of mRNA in human ejaculated sperm from normozoospermic donors: Relationship to sperm motility and capacitation. Mol Hum Reprod. 2004;10(7):535-41.
[18]Khazamipour N, Noruzinia M, Fatehmanesh P, Keyhanee M, Pujol P. MTHFR promoter hypermethylation in testicular biopsies of patients with non-obstructive azoospermia: The role of epigenetics in male infertility. Hum Reprod. 2009;24(9):2361-4.
[19]Wu W, Shen O, Qin Y, Niu X, Lu C, Xia Y, et al. Idiopathic male infertility is strongly associated with aberrant promoter methylation of methylenetetrahydrofolate reductase (MTHFR). PLoS One. 2010;5(11):e13884.
[20]Chan D, Cushnie DW, Neaga OR, Lawrance AK, Rozen R, Trasler JM. Strain-specific defects in testicular development and sperm epigenetic patterns in 5,10-methylenetetrahydrofolate reductase-deficient mice. Endocrinology. 2010;151(7):3363-73.
[21]Houshdaran S, Cortessis VK, Siegmund K, Yang A, Laird PW, Sokol RZ. Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm. PLoS One. 2007;2(12):e1289.
[22]Kumar R, Venkatesh S, Kumar M, Tanwar M, Shasmsi MB, Kumar R, et al. Oxidative stress and sperm mitochondrial DNA mutation in idiopathic oligoasthenozoospermic men. Indian J Biochem Biophys. 2009;46(2):172-7.
[23]Poplinski A, Tuttelmann F, Kanber D, Horsthemke B, Gromoll J. Idiopathic male infertility is strongly associated with aberrant methylation of MEST and IGF2/H19 ICR1. Int J Androl 2010;33(4):642-9.
[24]Hammoud SS, Purwar J, Pflueger C, Cairns BR, Carrell DT. Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility. Fertil Steril. 2010;94(5):1728-33.
[25]Kobayashi H, Sato A, Otsu E, Hiura H, Tomatsu C, Utsunomiya T, et al. Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients. Hum Mol Genet. 2007;16(21):2542-51.
[26]Li JY, Lees-Murdock DJ, Xu GL, Walsh CP. Timing of establishment of paternal methylation imprints in the mouse. Genomics. 2004;84(6):952-60.
[27]Baarends WM, Wassenaar E, van der Laan R, Hoogerbrugge J, Sleddens-Linkels E, Hoeijmakers JH, et al. Silencing of unpaired chromatin and histone H2A ubiquitination in mammalian meiosis. Mol Cell Biol. 2005;25(3):1041-53.
[28]Okada Y, Scott G, Ray MK, Mishina Y, Zhang Y. Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature. 2007;450(7166):119-23.
[29]Wu JY, Ribar TJ, Cummings DE, Burton KA, McKnight GS, Means AR. Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4. Nat Genet. 2000;25(4):448-52.
[30]Aoki VW, Emery BR, Liu L, Carrell DT. Protamine Levels vary between individual sperm cells of infertile human males and correlate with viability and DNA integrity. J Androl. 2006;27(6):890-8.
[31]Moghbelinejad S, Najafipour R, Hashjin AS. Comparison of Protamine 1 to Protamine 2 mRNA ratio and YBX2 gene mRNA content in testicular tissue of Fertile and Azoospermic Men. Int J Fertil Steril. 2015;9(3):338-45.
[32]Li C, Zheng L, Wang C, Zhou X. Absence of nerve growth factor and comparison of tyrosine kinase receptor A levels in mature spermatozoa from Oligoasthenozoospermic, Asthenozoospermic and Fertile men. Clin Chim Acta. 2010;411(19-20):1482-6.
[33]Guo X, Gui YT, Tang AF, Lu LH, Gao X, Cai ZM. Differential expression of VASA gene in ejaculated Spermatozoa from Normozoospermic men and patients with Oligozoospermia. Asian J Androl. 2007;9(3):339-44.
[34]Krawetz SA, Kruger A, Lalancette C, Tagett R, Anton E, Draghici S, et al. A survey of small RNAs in human sperm. Hum Reprod. 2011;26(12):3401-12.
[35]Papaioannou MD, Nef S. MicroRNAs in the testis: Building up male fertility. J Androl. 2010;31(1):26-33.
[36]Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259-69.
[37]Bjork JK, Sandqvist A, Elsing AN, Kotaja N, Sistonen L. The miR-18a member of Oncomir-1, targets heat shock transcription factor 2 in spermatogenesis. Development. 2010;137(19):3177-84.
[38]Barad O, Meiri E, Avniel A, Aharonov R, Barzilai A, Bentwich I, et al. MicroRNA expression detected by oligonucleotide microarrays: System establishment and expression profiling in human tissues. Genome Res. 2004;14(12):2486-94.
[39]Yu Z, Raabe T, Hecht NB. MicroRNA Mirn122a reduces expression of the Posttranscriptionally regulated germ cell transition protein 2 (Tnp2) messenger RNA (mRNA) by mRNA cleavage. Biol Reprod. 2005;73(3):427-33.
[40]Novotny GW, Sonne SB, Nielsen JE, Jonstrup SP, Hansen MA, Skakkebaek NE, et al. Translational repression of E2F1 mRNA in arcinoma in situ and normal testis correlates with expression of the miR-17-92 cluster. Cell Death Differ. 2007;14(4):879-82.
[41]Huang S, Li H, Ding X, Xiong C. Presence and characterization of cell-free seminal RNA in healthy individuals: Implications for noninvasive disease diagnosis and gene expression studies of the male reproductive system. Clin Chem. 2009;55(11):1967-76.
[42]Klattenhoff C, Theurkauf W. Biogenesis and germline functions of piRNAs. Development. 2008;135(1):3-9.
[43]Peters AH, O'Carroll D, Scherthan H, Mechtler K, Sauer S, Schofer C, et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell. 2001;107(3):323-37.
[44]Glaser S, Lubitz S, Loveland KL, Ohbo K, Robb L, Schwenk F, et al. The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis. Epigenetics Chromatin. 2009;2(1):5.
[45]Hayashi K, Yoshida K, Matsui Y. A histone H3 methyltransferase controls epigenetic events required for meiotic prophase. Nature. 2005;438(7066):374-8.
[46]Ciccone DN, Su H, Hevi S, Gay F, Lei H, Bajko J, et al. KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature. 2009;461(7262):415-8.
[47]An JY, Kim EA, Jiang Y, Zakrzewska A, Kim DE, Lee MJ, et al. UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination. Proc Natl Acad Sci USA. 2010;107(5):1912-7.
[48]Lu LY, Wu J, Ye L, Gavrilina GB, Saunders TL, Yu X. RNF8-dependent histone modifications regulate nucleosome removal during spermatogenesis. Dev cell. 2010;18(3):371-84.
[49]De La Fuente R, Baumann C, Fan T, Schmidtmann A, Dobrinski I, Muegge K. Lsh is required for meiotic chromosome synapsis and retrotransposon silencing in female germ cells. Nat Cell Biol. 2006;8(12):1448-54.
[50]Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, et al. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature. 2004;429(6994):900-3.
[51]Kato Y, Kaneda M, Hata K, Kumaki K, Hisano M, Kohara Y, et al. Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse. Hum Mol Genet. 2007;16(19):2272-80.
[52]Aravin AA, Sachidanandam R, Girard A, Fejes-Toth K, Hannon GJ. Developmentally regulated piRNA clusters implicate MILI in transposon control. Science. 2007;316(5825):744-7.
[53]Deng W, Lin H. MIVI, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Dev Cell. 2002;2(6):819-30.
[54]Carmell MA, Girard A, van de Kant HJ, Bourc'his D, Bestor TH, de Rooij DG, et al. MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev Cell. 2007;12(4):503-14.
[55]Shang E, Nickerson HD, Wen D, Wang X, Wolgemuth DJ. The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation. Development. 2007;134(19):3507-15.
[56]Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of adult disease: Strength of effects and biological basis. Int J Epidemiol. 2002;31(6):1235-9.