Journal
CELL REPORTS
Volume 24, Issue 13, Pages 3477-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.08.069
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Funding
- Foundation pour la Recherche Medicale (FRM)
- ANR Episperm3 program
- INCa libre program [RPT13001CCA]
- Universite Grenoble Alpes [ANR-15-IDEX-02]
- Fondation ARC Canc'air project [RAC16042CLA]
- Plan Cancer [CH7-INS15B66, ASC16012CSA]
- Worldwide Cancer Research foundation grant [16-0280]
- European Commission [FP7-PEOPLE-2011-ITN, PITN-GA-289880]
- La Ligue Nationale Contre Le Cancer
- FRM fellowship
- Inserm, GIS IBiSA, and Aix-Marseille Universite [ANR-10-INBS-0009-10]
- French National Research Agency ProFi grant [ANR-10-INBS-08-01]
- Wellcome Trust Cancer Development Fellowship [095751/Z/11/Z]
- MRC [MC_PC_13073, MR/N010051/1] Funding Source: UKRI
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Nuclear protein in testis (Nut) is a universal oncogenic driver in the highly aggressive NUT midline carcinoma, whose physiological function in male germ cells has been unclear. Here we show that expression of Nut is normally restricted to post-meiotic spermatogenic cells, where its presence triggers p300-dependent genome-wide histone H4 hyperacetylation, which is essential for the completion of histone-to-protamine exchange. Accordingly, the inactivation of Nut induces male sterility with spermatogenesis arrest at the histone-removal stage. Nut uses p300 and/or CBP to enhance acetylation of H4 at both K5 and K8, providing binding sites for the first bromodomain of Brdt, the testis-specific member of the BET family, which subsequently mediates genome-wide histone removal. Altogether, our data reveal the detailed molecular basis of the global histone hyperacetylation wave, which occurs before the final compaction of the male genome.
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