BRDT is an essential epigenetic regulator for proper chromatin organization, silencing of sex chromosomes and crossover formation in male meiosis

Abstract

The double bromodomain and extra-terminal domain (BET) proteins are critical epigenetic readers that bind to acetylated histones in chromatin and regulate transcriptional activity and modulate changes in chromatin structure and organization. The testis-specific BET member, BRDT, is essential for the normal progression of spermatogenesis as mutations in the Brdt gene result in complete male sterility. Although BRDT is expressed in both spermatocytes and spermatids, loss of the first bromodomain of BRDT leads to severe defects in spermiogenesis without overtly compromising meiosis. In contrast, complete loss of BRDT blocks the progression of spermatocytes into the first meiotic division, resulting in a complete absence of post-meiotic cells. Although BRDT has been implicated in chromatin remodeling and mRNA processing during spermiogenesis, little is known about its role in meiotic processes. Here we report that BRDT is an essential regulator of chromatin organization and reprograming during prophase I of meiosis. Loss of BRDT function disrupts the epigenetic state of the meiotic sex chromosome inactivation in spermatocytes, affecting the synapsis and silencing of the X and Y chromosomes. We also found that BRDT controls the global chromatin organization and histone modifications of the chromatin attached to the synaptonemal complex. Furthermore, the homeostasis of crossover formation and localization during pachynema was altered, underlining a possible epigenetic mechanism by which crossovers are regulated and differentially established in mammalian male genomes. Our observations reveal novel findings about the function of BRDT in meiosis and provide insight into how epigenetic regulators modulate the progression of male mammalian meiosis and the formation of haploid gametes.

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

“…In particular, H3K9me2 accumulates on sex chromosomes during the transition between the P to diplotene (D) stages, whereas H3K9me3 accumulates in the D stage [131,133]. Interestingly, the complete loss of bromodomain testis-specific protein (BRDT) results in a meiotic block of spermatogenesis that correlates to a reduction of H3K9me3 detection on XY chromosomes in P, negatively affecting the silencing of the X and Y chromosomes [134]. In addition, histone H2A ubiquitination is required for sex chromosomes gene inactivation in SPC.…”

Beyond Acephalic Spermatozoa: The Complexity of Intracytoplasmic Sperm Injection Outcomes

“…※ Loss-of-function. 4 BioMed Research International e BRDT protein, in comparison, is a member of the bromodomain and extraterminal subfamily and regulates meiosis in spermatocytes [39], the transcription of gene expression [40], and the elongation of sperm tails during spermatogenesis [41]. A loss of function of the mutated BRDT gene is associated with severe oligozoospermia and/or azoospermia disorders in western countries [40], but the negative impacts on male fertility were unable to be identified.…”

Genomic features of BRDT binding sites in gene units suggest transcriptional partners and specific epigenetic landscapes to regulate transcriptional activity during spermatogenesis

“…Based on the enriched biological processes identified in our GO analysis and potential relevance to BRDT"s functions as shown in previous studies from our laboratory (Berkovits et al, 2012;Berkovits & Wolgemuth, 2011;Manterola et al, 2018;Wang & Wolgemuth, 2016), we selected three critical processes and specific examples with which to localize the sites of BRDT binding, namely RNA processing/mRNA metabolic process, chromosome organization and spermatogenesis (Figure 3). In spermatocytes and spermatids, BRDT bound at the promoter of 106 and 43 genes, respectively, that are related to RNA processing and mRNA metabolic process, respectively ( Supplemental Table S5).…”