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Critical and different roles of DNA methylation in male germ cell development

Abstract : DNA methylation, associated with gene or transposable element (TE) repression, plays a key role in spermatogenesis. During germ cell development, their methylome is reprogrammed: somatic patterns are erased and germ cell-specific patterns are established. Three de novo DNA methyltransferases (DNMTs) are essential for shaping male germ cell DNA methylation in mice: DNMT3C and DNMT3A enzymes and DNMT3L co-factor. DNMT3C was shown to selectively methylate young TEs. However, the targets and function of DNMT3A was still unknown. During my PhD, I investigated the interplay between DNMT3A and DNMT3C in the epigenetic regulation of spermatogenesis. First (project 1), I reported a striking division of labor: while DNMT3C prevents TEs from interfering with meiosis, DNMT3A broadly methylates the genome—except DNMT3C-dependent TEs—and controls spermatogonial stem cell (SSC) plasticity. By single-cell RNA-seq and chromatin states profiling, I found that Dnmt3A mutant SSCs cannot differentiate due to spurious enhancer activation that enforces a stem cell gene program. I thus demonstrated a novel function for DNA methylation for SSC differentiation and life-long spermatogenesis supply. Second (project 2), I investigated the chromatin determinants of DNMT3C specificity towards young TEs. I found that these sequences present unique dynamics: first a bivalent H3K4me3-H3K9me3 enrichment, followed by a switch to H3K9me3-only. H3K9me3-enrichment was also a hallmark of the sequences that gain DNA methylation upon ectopic DNMT3C expression in cultured embryonic stem cells. As a whole, my work provided novel insights into the complexity of DNA methylation-based control of reproduction.
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Submitted on : Wednesday, December 15, 2021 - 4:12:08 PM
Last modification on : Tuesday, July 19, 2022 - 3:02:15 AM
Long-term archiving on: : Wednesday, March 16, 2022 - 7:23:13 PM

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  • HAL Id : tel-03482006, version 1

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Mathilde Dura. Critical and different roles of DNA methylation in male germ cell development. Genetics. Sorbonne Université, 2021. English. ⟨NNT : 2021SORUS187⟩. ⟨tel-03482006⟩

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