DOT1L regulates chromatin reorganization and gene expression during sperm differentiation

M. lina Blanco, Laila el Khattabi, Clara Gobé, Marion Crespo, Manon Coulée, Alberto de la Iglesia, C. me Ialy-Radio, Clementine Lapoujade, Maëlle Givelet, Marion Delessard, Ivan Seller-Corona, Kosuke Yamaguchi, Nadège Vernet, Fred van Leeuwen, Alban Lermine, Yuki Okada, Romain Daveau, Rafael Oliva, Pierre Fouchet, Ahmed ZiyyatDelphine Pflieger, Julie Cocquet

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

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.
Original languageEnglish
Article numbere56316
JournalEMBO reports
Volume24
Issue number6
Early online date2023
DOIs
Publication statusPublished - 5 Jun 2023

Keywords

  • H3K79 methylation
  • flagellum development
  • gene regulation
  • histone-to-protamine transition
  • spermatogenesis

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