Bromodomain-dependent stage-specific male genome programming by Brdt

Abstract

Male germ cell differentiation is a highly regulated multistep process initiated by the commitment of progenitor cells into meiosis and characterized by major chromatin reorganizations in haploid spermatids. We report here that a single member of the double bromodomain BET factors, Brdt, is a master regulator of both meiotic divisions and post-meiotic genome repackaging. Upon its activation at the onset of meiosis, Brdt drives and determines the developmental timing of a testis-specific gene expression program. In meiotic and post-meiotic cells, Brdt initiates a genuine histone acetylation-guided programming of the genome by activating essential genes and repressing a 'progenitor cells' gene expression program. At postmeiotic stages, a global chromatin hyperacetylation gives the signal for Brdt's first bromodomain to direct the genome-wide replacement of histones by transition proteins. Brdt is therefore a unique and essential regulator of male germ cell differentiation, which, by using various domains in a developmentally controlled manner, first drives a specific spermatogenic gene expression program, and later controls the tight packaging of the male genome.

RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain

“…BET proteins act as multidomain docking platforms that have a general role in transcription elongation by recruiting the positive transcription elongation factor b (P-TEFb) to acetylated chromatin (36,37), as well as tissue-specific functions. The cell type-specific roles have been highlighted by recent reports on BRDT-dependent transcription programs that regulate spermatogenesis (37-39) and BRD3-dependent recruitment of GATA1 in hematopoietic cells regulating maturation of erythroid, megakaryocyte, and mast cell lineages (23,40), as well as BRD2-dependent roles regulating differentiation of adipose tissue (25) and neurons (41).…”

The Impact of Bacterial Infections on Human Spermatozoa

“…Hyperacetylation of histone H4 occurs during the histone-to-protamine transition, perhaps causing a more open chromatin structure to facilitate histone replacement (93)(94)(95)(96) and serving as a signal for the bromodomain protein BRDT to initiate the histone-to-protamine transition (97). In mammals, reduced levels of histone H4 hyperacetylation correlates with impaired fertility (95,98).…”

Genetic association study ofRNF8andBRDTvariants with non-obstructive azoospermia in the Chinese Han population

“…Adult Brdt À/À mouse testes lack post-meiotic germ cells [Dhar et al 2012;Gaucher et al 2012;Jacobson et al 2000;Plaseski et al 2012;Pivot-Pajot et al 2003]. In this study, we genotyped 9 RNF8 SNPs and 5 BRDT SNPs to investigate whether genetic changes of the SNPs were risk factors for NOA.…”

“…The human bromo-domain, testis specific (BRDT) gene is located on chromosome 1p22.1 and regulates a suite of previous testis-specific genes during both meiosis and postmeiotic phases of spermiogenesis [Gaucher et al 2012] and is involved in chromatin remodeling through the post-meiotic phase. Adult Brdt À/À mouse testes lack post-meiotic germ cells [Dhar et al 2012;Gaucher et al 2012;Jacobson et al 2000;Plaseski et al 2012;Pivot-Pajot et al 2003].…”