The histone methyltransferase DOT1L regulates chromatin reorganization and gene expression during the postmeiotic differentiation of male germ cells
Résumé
Spermatozoa have a unique genome organization: their chromatin is almost completely devoid of histones and is formed instead of protamines which confer a higher level of compaction than nucleosomes and preserve paternal genome integrity until fertilization. Histone-to-protamine transition takes place in postmeiotic male germ cells called spermatids, and is indispensable for the production of functional spermatozoa and thus for male fertility. Here we show that the H3K79 (histone 3 lysine 79) methyltransferase DOT1L controls spermatid chromatin remodelling and subsequent reorganization and compaction of spermatozoon genome. Using a mouse model in which Dot1l is knocked-out in adult male germ cells, we found that the chromatin of Dot1l -knockout (KO) spermatozoa is less compact and characterized by a higher level of retained histones and of immature forms of protamine 2. Proteomic analyses performed on differentiating male germ cells reveal that Dot1l KO extensively modifies the spermatid chromatin prior to histone removal. By transcriptomics, we also show that Dot1l KO deregulates the expression of ~1500 genes, many of which are involved in other essential aspects of spermatid differentiation such as flagellum formation. As a consequence of all these chromatin and gene expression defects, Dot1l -KO spermatozoa have misshapen and less compact heads, and are less motile, which results in impaired fertility.
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