Epigenetic Transitions in Germ Cell Development and Meiosis

Kota, Satya K.; Feil, Robert

doi:10.1016/j.devcel.2010.10.009

Cited by 232 publications

(187 citation statements)

References 101 publications

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“…55 In male mouse fetuses, PGCs differentiate into prospermatogonia, enter mitotic arrest and reestablish methylation starting at E15; this is the time point at which paternal sex-specific imprints are set. 56,57 Consequently, this window is especially important for disruptions to loci that escape demethylation as well as resetting of global methylation in male offspring with any effects likely to be seen in the F2 generation. 33,58 Non-mammalian animals, in general, do not have imprinted genes.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Timing is everything

2011

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Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Timing is everything

2011

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“…Male germ cells undergo stem cell self-renewal, mitotic divisions in spermatogonial proliferation, genomic rearrangement by meiotic homologous recombination at the spermatocyte stage, and morphological changes of round spermatids into elongated spermatids to form mature spermatozoa (1)(2)(3). During spermiogenesis, nucleosomal histone proteins are replaced with transition nuclear proteins (TNPs) and subsequently, protamines, the major nucleosomal proteins in spermatozoa.…”

mentioning

confidence: 99%

MRG15 is required for pre-mRNA splicing and spermatogenesis

Iwamori

Tominaga

Sato

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Splicing can be epigenetically regulated and involved in cellular differentiation in somatic cells, but the interplay of epigenetic factors and the splicing machinery during spermatogenesis remains unclear. To study these interactions in vivo, we generated a germline deletion of MORF-related gene on chromosome 15 (MRG15), a multifunctional chromatin organizer that binds to methylated histone H3 lysine 36 (H3K36) in introns of transcriptionally active genes and has been implicated in regulation of histone acetylation, homology-directed DNA repair, and alternative splicing in somatic cells. Conditional KO (cKO) males lacking MRG15 in the germline are sterile secondary to spermatogenic arrest at the round spermatid stage. There were no significant alterations in meiotic division and histone acetylation. Specific mRNA sequences disappeared from 66 germ cell-expressed genes in the absence of MRG15, and specific intronic sequences were retained in mRNAs of 4 genes in the MRG15 cKO testes. In particular, introns were retained in mRNAs encoding the transition proteins that replace histones during sperm chromatin condensation. In round spermatids, MRG15 colocalizes with splicing factors PTBP1 and PTBP2 at H3K36me3 sites between the exons and single intron of transition nuclear protein 2 (Tnp2). Thus, our results reveal that MRG15 is essential for premRNA splicing during spermatogenesis and that epigenetic regulation of pre-mRNA splicing by histone modification could be useful to understand not only spermatogenesis but also, epigenetic disorders underlying male infertile patients.infertility | fertility defects | splicing defects | epigenetics | spermiogenesis S permatogenesis is a complex process involving several biological events and dramatic changes of chromatin structure. Male germ cells undergo stem cell self-renewal, mitotic divisions in spermatogonial proliferation, genomic rearrangement by meiotic homologous recombination at the spermatocyte stage, and morphological changes of round spermatids into elongated spermatids to form mature spermatozoa (1-3). During spermiogenesis, nucleosomal histone proteins are replaced with transition nuclear proteins (TNPs) and subsequently, protamines, the major nucleosomal proteins in spermatozoa. Moreover, epigenetic modifications, such as histone methylation, dramatically change throughout spermatogenesis (3, 4).Pre-mRNA splicing generates protein diversity and is involved in the regulation of cellular differentiation (5, 6). Recent advances have shown that histone modifications regulate alternative splicing through recruitment of splicing regulators via chromatin binding proteins, such as MORF-related gene on chromosome 15 (MRG15) (7). Histone H3 lysine 36 (H3K36) is methylated proximal to tissuespecific splicing regions (8-12). MRG15 specifically recognizes the methylated H3K36 and recruits polypyrimidine tract binding protein (PTB) at intronic splicing silencer elements near an exon to suppress exon insertions into mRNA (7). MRG15 is also a component of histone acetyltransfe...

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“…Meiosis is the cornerstone of sexual reproduction, as it generates haploid cells (gametes or spores) required for the formation of a diploid organism genetically distinct from both parents. 55 Substantial chromatin changes, including modifications of histones, are observed prior to and during meiosis, as well as during the maturation of gametes (gametogenesis). 55 A yeast strain specifically impaired in ubiquitylation of H2B (through mutation of the target lysine to arginine, K123R) was found to be unable to form spores on account of meiotic prophase arrest.…”

Section: H2bub1 In Gametogenesismentioning

confidence: 99%

“…55 Substantial chromatin changes, including modifications of histones, are observed prior to and during meiosis, as well as during the maturation of gametes (gametogenesis). 55 A yeast strain specifically impaired in ubiquitylation of H2B (through mutation of the target lysine to arginine, K123R) was found to be unable to form spores on account of meiotic prophase arrest. 7 Detailed characterization of the H2B K123R mutant in a rapidly sporulating genetic background revealed that the formation of double-stranded breaks (DSBs) during meiotic pachytene is delayed, and the frequencies of DSBs at certain loci were reduced.…”

Section: H2bub1 In Gametogenesismentioning

confidence: 99%