Nut Directs p300-Dependent, Genome-Wide H4 Hyperacetylation in Male Germ Cells.
journal contributionposted on 2019-07-03, 16:03 authored by H Shiota, S Barral, T Buchou, M Tan, Y Couté, G Charbonnier, N Reynoird, F Boussouar, M Gérard, M Zhu, L Bargier, D Puthier, F Chuffart, E Bourova-Flin, S Picaud, P Filippakopoulos, A Goudarzi, Z Ibrahim, D Panne, S Rousseaux, Y Zhao, S Khochbin
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.
The S.K. laboratory is supported by a grant from the Foundation pour la Recherche Medicale (FRM), “analyse bio-informatique pour la recherche en biologie” program, as well as by the ANR Episperm3 program and by INCa libre program (RPT13001CCA). Additional support came from the Université Grenoble Alpes (ANR-15-IDEX-02) LIFE and SYMER programs, as well as from Fondation ARC “Canc’air” project (RAC16042CLA) and Plan Cancer (CH7-INS15B66 and ASC16012CSA). Z.I. and D.P. were supported by a Worldwide Cancer Research foundation grant (16-0280) to D.P. H.S. was a recipient of a Marie Curie Initial Training Network funded by European Commission (FP7-PEOPLE-2011-ITN and PITN-GA-289880) for 3 years and then supported by La Ligue Nationale Contre Le Cancer for a 4th year of PhD pursuit. G.C. is a bioinformatic expert benefiting from a FRM fellowship. Mice were bred in the High Technology Animal Facility (PHTA) of Grenoble University with the help of Natacha Pitoun and Kevin Escot. The TGML Platform is supported by grants from Inserm, GIS IBiSA, and Aix-Marseille Université (ANR-10-INBS-0009-10). We are grateful to Hortense Vachon for her help with library preparation and sequencing. The proteomic analyses were partially supported by the French National Research Agency ProFi grant (ANR-10-INBS-08-01). P.F. and S.P. were supported by a Wellcome Trust Cancer Development Fellowship (095751/Z/11/Z). Y.C. thanks the support of the discovery platform and informatics group at EDyP. Most computations presented in this paper were performed using the GRICAD infrastructure (https://gricad.univ-grenoble-alpes.fr).
CitationCell Reports, 2018, 24 (13), pp. 3477-3487.e6
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology
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