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

Abstract : Graphical Abstract Highlights d Nut is a post-meiotically expressed gene that is critical for male fertility d Nut recruits p300 and/or CBP to enhance histone H4K5 and H4K8 acetylation d Nut-mediated histone hyperacetylation is required for histone-to-protamine transition A transcription-independent histone hyperacetylation is associated with near-total histone replacement during mouse spermatogenesis. Shiota et al. show the oncogenic factor Nut is expressed in post-meiotic male germ cells, where it recruits p300 and/or CBP and enhances histone H4K5 and H4K8 acetylation, leading to histone-to-protamine replacement. 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 hyper-acetylation, which is essential for the completion of histone-to-protamine exchange. Accordingly, theinactivation 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.