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Nucleic Acids Res. 2020 Mar 17. pii: gkaa163. doi: 10.1093/nar/gkaa163. [Epub ahead of print]

Multi-omic analysis of gametogenesis reveals a novel signature at the promoters and distal enhancers of active genes.

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Univ. Grenoble Alpes, CEA, Inserm, IRIG-BGE, 38000 Grenoble, France.
Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, CEA, INRA, Université Paris Saclay, MetaboHUB, 91191 Gif-sur-Yvette, France.
Institut Cochin, INSERM U1016, CNRS UMR8104, Université de Paris, 75014 Paris, France.
CNRS UMR 5309, Inserm U1209, Université Grenoble Alpes, Institute for Advanced Biosciences, 38000 Grenoble, France.
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, 2 rue Gaston Crémieux, CP 5706, 91057 Evry Cedex, France.
Univ. Grenoble Alpes, CEA, INSERM, Biosciences and Biotechnology Institute of Grenoble, Biology of Cancer and Infection UMR_S 1036, 38000 Grenoble, France.
CNRS, IRIG-BGE, 38000 Grenoble, France.


Epigenetic regulation of gene expression is tightly controlled by the dynamic modification of histones by chemical groups, the diversity of which has largely expanded over the past decade with the discovery of lysine acylations, catalyzed from acyl-coenzymes A. We investigated the dynamics of lysine acetylation and crotonylation on histones H3 and H4 during mouse spermatogenesis. Lysine crotonylation appeared to be of significant abundance compared to acetylation, particularly on Lys27 of histone H3 (H3K27cr) that accumulates in sperm in a cleaved form of H3. We identified the genomic localization of H3K27cr and studied its effects on transcription compared to the classical active mark H3K27ac at promoters and distal enhancers. The presence of both marks was strongly associated with highest gene expression. Assessment of their co-localization with transcription regulators (SLY, SOX30) and chromatin-binding proteins (BRD4, BRDT, BORIS and CTCF) indicated systematic highest binding when both active marks were present and different selective binding when present alone at chromatin. H3K27cr and H3K27ac finally mark the building of some sperm super-enhancers. This integrated analysis of omics data provides an unprecedented level of understanding of gene expression regulation by H3K27cr in comparison to H3K27ac, and reveals both synergistic and specific actions of each histone modification.


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