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Cell Rep. 2018 Sep 25;24(13):3477-3487.e6. doi: 10.1016/j.celrep.2018.08.069.

Nut Directs p300-Dependent, Genome-Wide H4 Hyperacetylation in Male Germ Cells.

Author information

1
CNRS UMR 5309, Inserm U1209, Université Grenoble Alpes, Institute for Advanced Biosciences, Grenoble 38700, France.
2
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P.R. China.
3
Université Grenoble Alpes, CEA, Inserm U1038, CEA, BIG-BGE, Grenoble 38000, France.
4
TGML, platform IbiSA, Aix Marseille Université, Inserm U1090, TAGC, Marseille, France.
5
CEA, iBiTec-S, Gif-sur-Yvette 91191, France.
6
Structural Genomics Consortium & Ludwig Institute for Cancer Research, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
7
EMBL Grenoble, BP 181, 71 Avenue des Martyrs, 38042 Grenoble Cedex 9, France.
8
EMBL Grenoble, BP 181, 71 Avenue des Martyrs, 38042 Grenoble Cedex 9, France; Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK.
9
Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
10
CNRS UMR 5309, Inserm U1209, Université Grenoble Alpes, Institute for Advanced Biosciences, Grenoble 38700, France. Electronic address: saadi.khochbin@univ-grenoble-alpes.fr.

Abstract

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.

KEYWORDS:

BRD4-NUT; cancer testis; histone post-translational modifications; histone variants; protamines; spermiogenesis; testis specific; transition proteins

PMID:
30257209
DOI:
10.1016/j.celrep.2018.08.069
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