The role of the double bromodomain-containing BET genes during mammalian spermatogenesis.

The double bromodomain-containing BET (bromodomain and extra terminal) family of proteins is highly conserved from yeast to humans and consists not just of transcriptional regulators but also histone-interacting chromatin remodelers. The four mammalian BET genes are each expressed at unique times during spermatogenesis, and the testis-specific gene Brdt is essential for spermatogenesis. Loss of the first bromodomain of BRDT results in improper/incomplete spermatid elongation and severely morphologically defective sperm. The elongation defects observed in mutant spermatids can be directly tied to altered postmeiotic chromatin architecture. BRDT is required for creation/maintenance of the chromocenter of round spermatids, a structure that forms just after completion of meiosis. The chromocenter creates a defined topology in spermatids, and the presence of multiple chromocenters rather than a single intact chromocenter correlates with loss of spermatid polarity, loss of heterochromatin foci at the nuclear envelope, and loss of proper spermatid elongation. BRDT is not only essential for proper chromatin organization but also involved in regulation of transcription and in cotranscriptional processing. That is, transcription and alternative splicing are altered in spermatocytes and spermatids that lack full-length BRDT. Additionally, the transcription of mRNAs with short 3' UTRs, which is characteristic of round spermatids, is also altered. Examination of the genes regulated by BRDT yields many possible targets that could in part explain the morphologically abnormal sperm produced by the BRDT mutant testes. Thus, BRDT and possibly the other BET genes are required for proper spermatogenesis, which opens up the possibility that the recently discovered small molecule inhibitors of the BET family could be useful as reversible male contraceptives.