Chromatin environment-dependent effects of DOT1L on gene expression in male germ cells
Coulée, Manon (Université Paris Cité)
de la Iglesia, Alberto (Université Paris Cité)
Blanco, Mélina (Université Paris-Saclay)
Gobé, Clara (Université Paris Cité)
Lapoujade, Clémentine (Université Paris-Saclay)
Ialy-Radio, Côme (Université Paris Cité)
Álvarez-González, Lucía (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Meurice, Guillaume (MOABI)
Ruiz-Herrera Moreno, Aurora (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Fouchet, Pierre (Université Paris-Saclay)
Cocquet, Julie (Université Paris Cité)
El Khattabi, Laïla (Sorbonne Université)

Fecha:	2025
Resumen:	The H3K79 methyltransferase DOT1L is essential for multiple aspects of mammalian development where it has been shown to regulate gene expression. Here, by producing and integrating epigenomic and spike-in RNA-seq data, we decipher the molecular role of DOT1L during mouse spermatogenesis and show that it has opposite effects on gene expression depending on chromatin environment. On one hand, DOT1L represses autosomal genes that are devoid of H3K79me2 at their bodies and located in H3K27me3-rich/H3K27ac-poor environments. On the other hand, it activates the expression of genes enriched in H3K79me2 and located in H3K27me3-poor/H3K27ac-rich environments, predominantly X chromosome-linked genes, after meiosis I. This coincides with a significant increase in DOT1L expression at this stage and a genome-wide acquisition of H3K79me2, particularly on the sex chromosomes. Taken together, our results show that H3K79me2 positively correlates with male germ cell genetic program throughout spermatogenesis, with DOT1L predominantly inhibiting rather than activating gene expression. Interestingly, while DOT1L appears to directly regulate the (re)activation of X genes following meiotic sex chromosome inactivation, it also controls the timely expression of (autosomal) differentiation genes during spermatogenesis.
Ayudas:	Agencia Estatal de Investigación PID2020-112557GB-I00 Agencia Estatal de Investigación CGL2017-83802-P Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00122 Agencia Estatal de Investigación PRE-2018-083257
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Histone post-translational modifications ; Epigenomics ; Spermatogenesis
Publicado en:	Communications Biology, Vol. 8 (January 2025) , art. 138, ISSN 2399-3642

DOI: 10.1038/s42003-024-07393-x
PMID: 39875559

17 p, 2.9 MB

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