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bioRxiv · 10.1101/2021.04.19.440465

DNMT3A-dependent DNA methylation is required for spermatogonial stem cells to commit to spermatogenesis

Dura, M.·Teissandier, A.·Armand, M.·Barau, J.·Bonneville, L.·Weber, M.·Baudrin, L. G.·Lameiras, S.·Bourc'his, D.
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Abstract

DNA methylation plays a critical role in spermatogenesis, as evidenced by the male sterility of DNA methyltransferase (DNMT) mutant mice. Here, we report a striking division of labor in the establishment of the methylation landscape of male germ cells and its functions in spermatogenesis: while DNMT3C is essential for preventing retrotransposons from interfering with meiosis, DNMT3A broadly methylates the genome--at the exception of DNMT3C-dependent retrotransposons--and controls spermatogonial stem cell (SSC) plasticity. By reconstructing developmental trajectories through single-cell RNA-seq and by profiling chromatin states, we found that Dnmt3A mutant SSCs can only self-renew and no longer differentiate due to spurious enhancer activation that enforces an irreversible stem cell gene program. We therefore provide a novel function for DNA methylation in male fertility: the epigenetic programming of SSC commitment to differentiation and to life-long spermatogenesis supply.

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Dura, M., Teissandier, A., Armand, M., Barau, J., Bonneville, L., Weber, M., Baudrin, L. G., Lameiras, S., Bourc'his, D.. 2021-04-19. DNMT3A-dependent DNA methylation is required for spermatogonial stem cells to commit to spermatogenesis. https://doi.org/10.1101/2021.04.19.440465

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