DOT1L regulates chromatin reorganization and gene expression during sperm differentiation.

Autor: Blanco M; Université Paris Cité, INSERM, CNRS, Institut Cochin, Paris, France., El Khattabi L; Université Paris Cité, INSERM, CNRS, Institut Cochin, Paris, France.; Chromosomal Genomics Unit, Medical Genetics Department, Sorbonne Université and APHP, Hôpital Armand Trousseau, Paris, France., Gobé C; Université Paris Cité, INSERM, CNRS, Institut Cochin, Paris, France., Crespo M; University Grenoble Alpes, CEA, INSERM, UA13 BGE, CNRS, CEA, FR2048, Grenoble, France.; ADLIN Science, Pépinière « Genopole Entreprises », Evry, France., Coulée M; Université Paris Cité, INSERM, CNRS, Institut Cochin, Paris, France., de la Iglesia A; Université Paris Cité, INSERM, CNRS, Institut Cochin, Paris, France.; Molecular Biology of Reproduction and Development Research Group, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Fundació Clínic per a la Recerca Biomèdica, Universitat de Barcelona (UB), Barcelona, Spain., Ialy-Radio C; Université Paris Cité, INSERM, CNRS, Institut Cochin, Paris, France., Lapoujade C; Université de Paris and Université Paris-Saclay, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Laboratoire des Cellules Souches Germinales, Fontenay-aux-Roses, France., Givelet M; Université de Paris and Université Paris-Saclay, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Laboratoire des Cellules Souches Germinales, Fontenay-aux-Roses, France., Delessard M; Université Paris Cité, INSERM, CNRS, Institut Cochin, Paris, France., Seller-Corona I; Université Paris Cité, INSERM, CNRS, Institut Cochin, Paris, France., Yamaguchi K; Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan., Vernet N; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Génétique Fonctionnelle et Cancer, CNRS, INSERM, Université de Strasbourg, Illkirch, France., Van Leeuwen F; Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands., Lermine A; MOABI-APHP Bioinformatics Platform-I&D-DSI, Assistance Publique-Hôpitaux de Paris, Paris, France., Okada Y; Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan., Daveau R; MOABI-APHP Bioinformatics Platform-I&D-DSI, Assistance Publique-Hôpitaux de Paris, Paris, France., Oliva R; Molecular Biology of Reproduction and Development Research Group, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Fundació Clínic per a la Recerca Biomèdica, Universitat de Barcelona (UB), Barcelona, Spain.; Biochemistry and Molecular Genetics Service, Clinic Barcelona, Barcelona, Spain., Fouchet P; Université de Paris and Université Paris-Saclay, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Laboratoire des Cellules Souches Germinales, Fontenay-aux-Roses, France., Ziyyat A; Université Paris Cité, INSERM, CNRS, Institut Cochin, Paris, France.; Service d'Histologie, d'Embryologie, Biologie de la Reproduction, AP-HP, Hôpital Cochin, Paris, France., Pflieger D; University Grenoble Alpes, CEA, INSERM, UA13 BGE, CNRS, CEA, FR2048, Grenoble, France., Cocquet J; Université Paris Cité, INSERM, CNRS, Institut Cochin, Paris, France.
Jazyk: angličtina
Zdroj: EMBO reports [EMBO Rep] 2023 Jun 05; Vol. 24 (6), pp. e56316. Date of Electronic Publication: 2023 Apr 26.
DOI: 10.15252/embr.202256316
Abstrakt: 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.
(© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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