DOT1L regulates chromatin reorganization and gene expression during sperm differentiation

Mélina Blanco (1) , Laila El Khattabi , Clara Gobé , Marion Crespo , Manon Coulée , Alberto de la Iglesia , Côme Ialy-Radio , Clementine Lapoujade , Maëlle Givelet , Marion Delessard , Ivan Seller-Corona , Kosuke Yamaguchi , Nadège Vernet (2) , Fred van Leeuwen , Alban Lermine , Yuki Okada , Romain Daveau , Rafael Oliva , Pierre Fouchet , Ahmed Ziyyat , Delphine Pflieger , Julie Cocquet

1 IC UM3 (UMR 8104 / U1016) - Institut Cochin
2 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

Abstract Spermatozoa have a unique genome organization. Their chromatin is almost completely devoid of histones and is formed instead of protamines, which confer a high level of compaction and preserve paternal genome integrity until fertilization. Histone‐to‐protamine transition takes place in spermatids and is indispensable for the production of functional sperm. Here, we show that the H3K79‐methyltransferase DOT1L controls spermatid chromatin remodeling and subsequent reorganization and compaction of the spermatozoon genome. Using a mouse model in which Dot1l is knocked‐out (KO) in postnatal male germ cells, we found that Dot1l ‐KO sperm chromatin is less compact and has an abnormal content, characterized by the presence of transition proteins, immature protamine 2 forms and a higher level of histones. Proteomic and transcriptomic analyses performed on spermatids reveal that Dot1l ‐KO modifies the chromatin prior to histone removal and leads to the deregulation of genes involved in flagellum formation and apoptosis during spermatid differentiation. As a consequence of these chromatin and gene expression defects, Dot1l ‐KO spermatozoa have less compact heads and are less motile, which results in impaired fertility.

Domaines: Sciences du Vivant [q-bio]

Mélina Blanco, Laila El Khattabi, Clara Gobé, Marion Crespo, Manon Coulée, et al.. DOT1L regulates chromatin reorganization and gene expression during sperm differentiation. EMBO Reports, 2023, 24 (6), ⟨10.15252/embr.202256316⟩. ⟨hal-04253697⟩