Abstract
Original language | English |
---|---|
Article number | e56316 |
Journal | EMBO reports |
Volume | 24 |
Issue number | 6 |
Early online date | 2023 |
DOIs | |
Publication status | Published - 5 Jun 2023 |
Keywords
- H3K79 methylation
- flagellum development
- gene regulation
- histone-to-protamine transition
- spermatogenesis
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In: EMBO reports, Vol. 24, No. 6, e56316, 05.06.2023.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - DOT1L regulates chromatin reorganization and gene expression during sperm differentiation
AU - Blanco, M. lina
AU - el Khattabi, Laila
AU - Gobé, Clara
AU - Crespo, Marion
AU - Coulée, Manon
AU - de la Iglesia, Alberto
AU - Ialy-Radio, C. me
AU - Lapoujade, Clementine
AU - Givelet, Maëlle
AU - Delessard, Marion
AU - Seller-Corona, Ivan
AU - Yamaguchi, Kosuke
AU - Vernet, Nadège
AU - van Leeuwen, Fred
AU - Lermine, Alban
AU - Okada, Yuki
AU - Daveau, Romain
AU - Oliva, Rafael
AU - Fouchet, Pierre
AU - Ziyyat, Ahmed
AU - Pflieger, Delphine
AU - Cocquet, Julie
N1 - Funding Information: We would like to thank Cochin Institute (INSERM U1016, CNRS UMR8104, Universite Paris Cité) core facilities, in particular, Alain Schmitt from the electron microscopy platform, and all the staff from the animal house, histology (HistIM), genomic (GENOM'IC), cytometry (CYBIO), and imaging (IMAG'IC) core facilities. We would also like to thank Guillaume Meurice for advices on bioinformatics analyses, and Aminata Touré and Marjorie Whitfield for advices and discussion on sperm morphology and motility analyses. M.Cr. and D.P. are grateful to their colleagues in EDyP for their support on LC–MS instruments and in informatics. This work was supported by the Agence Nationale de la Recherche (ANR‐17‐CE12‐0004‐01 to J.C., ANR‐21‐CE44‐0035 to D.P.), the Fondation pour la Recherche Médicale (SPF201909009274 to C.G.) and grants from Institut Cochin (PIC‐2018 to L.E.K.), “Ministerio de Economía y competitividad” FI17/00224 to A.I., and “Ministerio de Ciencia e Innovación” PI20/00936 to R.O. and MV20/00026 to A.I. M.B and M.Co. received a PhD funding from Université Paris Cité, M.Cr., from University Grenoble Alps (UGA). The proteomic experiments were partially supported by Agence Nationale de la Recherche under projects ProFI (Proteomics French Infrastructure, ANR‐10‐INBS‐08) and GRAL, a program from the Chemistry Biology Health (CBH) Graduate School of University Grenoble Alpes (ANR‐17‐EURE‐0003). This publication is also based upon work from COST Action CA20119 (ANDRONET) supported by European Cooperation in Science and Technology ( www.cost.eu ). Funding Information: We would like to thank Cochin Institute (INSERM U1016, CNRS UMR8104, Universite Paris Cité) core facilities, in particular, Alain Schmitt from the electron microscopy platform, and all the staff from the animal house, histology (HistIM), genomic (GENOM'IC), cytometry (CYBIO), and imaging (IMAG'IC) core facilities. We would also like to thank Guillaume Meurice for advices on bioinformatics analyses, and Aminata Touré and Marjorie Whitfield for advices and discussion on sperm morphology and motility analyses. M.Cr. and D.P. are grateful to their colleagues in EDyP for their support on LC–MS instruments and in informatics. This work was supported by the Agence Nationale de la Recherche (ANR-17-CE12-0004-01 to J.C., ANR-21-CE44-0035 to D.P.), the Fondation pour la Recherche Médicale (SPF201909009274 to C.G.) and grants from Institut Cochin (PIC-2018 to L.E.K.), “Ministerio de Economía y competitividad” FI17/00224 to A.I., and “Ministerio de Ciencia e Innovación” PI20/00936 to R.O. and MV20/00026 to A.I. M.B and M.Co. received a PhD funding from Université Paris Cité, M.Cr., from University Grenoble Alps (UGA). The proteomic experiments were partially supported by Agence Nationale de la Recherche under projects ProFI (Proteomics French Infrastructure, ANR-10-INBS-08) and GRAL, a program from the Chemistry Biology Health (CBH) Graduate School of University Grenoble Alpes (ANR-17-EURE-0003). This publication is also based upon work from COST Action CA20119 (ANDRONET) supported by European Cooperation in Science and Technology (www.cost.eu). Publisher Copyright: © 2023 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2023/6/5
Y1 - 2023/6/5
N2 - 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.
AB - 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.
KW - H3K79 methylation
KW - flagellum development
KW - gene regulation
KW - histone-to-protamine transition
KW - spermatogenesis
UR - http://www.scopus.com/inward/record.url?scp=85153523047&partnerID=8YFLogxK
U2 - https://doi.org/10.15252/embr.202256316
DO - https://doi.org/10.15252/embr.202256316
M3 - Article
C2 - 37099396
SN - 1469-221X
VL - 24
JO - EMBO reports
JF - EMBO reports
IS - 6
M1 - e56316
ER -