BRDT is an essential epigenetic regulator for proper chromatin organization, silencing of sex chromosomes and crossover formation in male meiosis.Librarian's Comment : Human oocytes remain arrested at prophase I (the first stage of meiosis) from fetal life to just before ovulation. Not surprisingly, the (epi)genetic regulation of prophase I chromosomes is essential for the formation of healthy female gametes. But what about their male counterparts? Does the dramatically shorter sperm prophase I require any dedicated (epi)genetic control? The answer seems to be yes. This study (using the mouse model) establishes that the testis-specific epigenetic regulator BRDT is required, in late prophase I, for the correct organization of the sperm chromosomes and for normal meiotic recombination. The mechanistic insight brought by these observations helps to clarify the previously reported association between genetic variants in the BRDT gene and spermatogenic defects in infertile men.
Published in : PLoS genetics
Authors : Manterola M, Brown TM, Oh MY, Garyn C, Gonzalez BJ, Wolgemuth DJ
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.