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

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.

Emerging entities in NUTM1‐rearranged neoplasms

“…Until recently, very little was known regarding the normal function of NUTM1. It is now known to be critical for male fertility and is expressed in postmeiotic male germ cells where it recruits the HATs p300 and/or CBP and enables histone H4K5 and H4K8 acetylation . This stimulates the transcription of a subset of genes involved in transcriptional shutdown in preparation for the striking genome‐wide chromatin remodeling process within condensing spermatids, whereby histones are evicted and replaced by transition proteins and small basic proteins called protamines.…”

“…It is now known to be critical for male fertility and is expressed in postmeiotic male germ cells where it recruits the HATs p300 and/or CBP and enables histone H4K5 and H4K8 acetylation. 20 This stimulates the transcription of a subset of genes involved in transcriptional shutdown in preparation for the striking genome-wide chromatin remodeling process within condensing spermatids, whereby histones are evicted and replaced by transition proteins and small basic proteins called protamines. Notably, postmeiotic spermatids coexpress NUTM1 and the BRD family member bromodomain testis-specific protein (BRDT), 21 thus the megadomain-spanning chromatin hyperacetylation and transcriptional repression of genes involved in differentiation observed in NCs (see below) may be seen as a somatic aberration of this crucial male germline phenomenon.…”

Histone Post-Translational Modifications and CircRNAs in Mouse and Human Spermatozoa: Potential Epigenetic Marks to Assess Human Sperm Quality

“…Recently it has been shown that Nut, a testis-specific factor exclusively expressed in post-meiotic cells, interacts with CBP/p300 HAT to enhance acetylation of H4 at both K5 and K8 [164] (Figure 5F). Interestingly, acetylation of histone H4 on residues K5 and K8 provides a binding site for the BRDT.…”

RNA-Guided Genomic Localization of H2A.L.2 Histone Variant

“…In mammals, a near genome-wide histone removal occurs during the postmeiotic stages of spermatogenesis in specific cell types known as elongating and condensing spermatids. Histone removal is also preceded by a genome-wide histone acetylation, especially on H4 lysines 5 and 8 [1], creating a specific binding site for the first bromodomain of the testis-specific BET factor, Brdt. We previously demonstrated that Brdt is, in turn, required for histone removal, and is involved in the loading of transition proteins and protamines into nucleosomes [1][2][3].…”

“…Histone removal is also preceded by a genome-wide histone acetylation, especially on H4 lysines 5 and 8 [1], creating a specific binding site for the first bromodomain of the testis-specific BET factor, Brdt. We previously demonstrated that Brdt is, in turn, required for histone removal, and is involved in the loading of transition proteins and protamines into nucleosomes [1][2][3]. Our work on the involvement of histone variants in this process also led to the discovery of a series of testis-specific H2A and H2B histone variants as potentially interesting candidates in the control of postmeiotic male genome organization [4].…”