DOT1L regulates chromatin reorganization and gene expression during sperm differentiation. undefined

The H3K79 methyltransferase DOT1L has been implicated in many biological processes, including development and mixed-lineage leukemias, but, despite a high expression in postmeiotic male gametes, its role during spermatogenesis remains unknown. In the present study, we produced a mouse model in which Dot1l was knocked-out (KO) in post-natal male gametes. We showed that Dot1l is required for the production of functional spermatozoa, and that its KO impairs male fertility. By multi-omics analyses we found that Dot1l-KO disturbs the chromatin reorganization and compaction process which normally takes place towards the end of spermatogenesis, but also deregulates mitochondrial metabolism, in particular acyl-CoA levels. Finally, we found that DOT1L protein interacts with the Pyruvate Dehydrogenase Complex, a mitochondrial complex involved in the conversion of pyruvate into acetyl-CoA, which we also detected in male gametes’ nucleus. Overall, our data demonstrate the critical role of DOT1L during the differentiation of post-meiotic gametes and show a link between DOT1L and mitochondrial metabolism.