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.
Highlights
The bromodomain is a highly conserved motif that recognizes and binds to acetylated lysine residues, a key step in reading epigenetic marks
In post-meiotic cells, BRDT is involved in chromatin organization and transcriptional regulation through its first bromodomain motif, as loss of the BD1 results in a truncated BRDT protein that fully interrupts the differentiation of the germ cells during the process of spermiogenesis
We investigated how BRDT controls meiosis by examining its subcellular localization during prophase I as well as the meiotic consequences observed with the loss of BRDT function
Summary
The bromodomain is a highly conserved motif that recognizes and binds to acetylated lysine residues, a key step in reading epigenetic marks. Among the bromodomain-containing proteins, the BET (bromodomain and extra-terminal) subfamily is characterized by the presence of two bromodomains (hereafter referred to as BD1 and BD2) that bind to acetylated histones, and an extra terminal (ET) domain, which functions as a functional module for protein–protein interactions [1, 2]. There are four BET members, BRD2, BRD3, BRD4 and BRDT, and among them, BRD4 and BRDT are structurally more similar in that they have a region of homology at the carboxyl-terminus, referred to as the C-terminal domain (CTD). The BET proteins are epigenetic regulators with multiple functions in chromatin organization and transcriptional regulation. They direct the recruitment of diverse regulatory complexes to discrete regions in the genome, by mediating the tethering of protein complexes to acetylated histones and other proteins. The BET proteins have received increasing attention due to their important implications in a wide range of human diseases [3], and for being therapeutic targets of BET protein inhibitors [4]
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