DOT1L regulates chromatin reorganization and gene expression during sperm differentiation

EMBO Reports - Tập 24 Số 6 - 2023
M. Andrés Blanco1, Laïla El Khattabi2,1, Clara Gobé1, Marion Crespo3,4, Manon Coulée1, Alberto de la Iglesia5,1, Côme Ialy‐Radio1, Clémentine Lapoujade6, Maëlle Givelet6, Marion Delessard1, Ivan Seller‐Corona1, Kosuke Yamaguchi7, Nadège Vernet8, Fred van Leeuwen9, Alban Lermine10, Yuki Okada7, Romain Daveau10, Rafael Oliva11,5, Pierre Fouchet6, Ahmed Ziyyat12,1, Delphine Pflieger4, Julie Cocquet1
1Université Paris Cité, INSERM, CNRS, Institut Cochin Paris France
2Chromosomal Genomics Unit, Medical Genetics Department, Sorbonne Université and APHP, Hôpital Armand Trousseau Paris France
3ADLIN Science, Pépinière « Genopole Entreprises » Evry France
4University Grenoble Alpes, CEA, INSERM, UA13 BGE, CNRS, CEA, FR2048 Grenoble France
5Molecular 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
6Université 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
7Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan
8Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Génétique Fonctionnelle et Cancer, CNRS, INSERM Université de Strasbourg Illkirch France
9Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands
10MOABI‐APHP Bioinformatics Platform‐I&D‐DSI, Assistance Publique‐Hôpitaux de Paris Paris France
11Biochemistry and Molecular Genetics Service, Clinic Barcelona Barcelona Spain
12Service d'Histologie, d'Embryologie, Biologie de la Reproduction, AP‐HP, Hôpital Cochin Paris France

Tóm tắt

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.

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EMBO Reports

Tập 24 Số 6

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