The H3K79 methyltransferase DOT1L has pleiotropic regulatory effects during spermatogenesis. undefined

DOT1L is the only H3K79 methyltransferase. Mechanistically, it has been shown to regulate gene expression but also cell cycle progression, or chromatin organization. DOT1L is expressed almost ubiquitously during development and, at the adult stage, it is most highly expressed in post-meiotic male germ cells called spermatids. Using a mouse model in which Dot1l is knocked-out (KO) in postnatal male germ cells, we found that Dot1l-KO leads to multiple spermatogenesis defects which impair male fertility. To understand the origin of these defects and investigate the role and dynamics of Dot1l and H3K79me2 during spermatogenesis. At the molecular level, integrated transcriptomic and epigenomic analyses revealed that DOT1L has opposite effects on gene expression depending on their chromatin environment, promoting the expression of hundreds of genes, in particular of XY-encoded genes, while repressing a higher number of other genes.