The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation

Brd4 is a double bromodomain-containing protein that binds preferentially to acetylated chromatin. It belongs to the BET (bromodomains and extraterminal) family that includes mammalian Brd2, Brd3, Brd4, Brdt, Drosophila Fsh, yeast Bdf1, Bdf2, and corresponding homologues in other species. Brd4 is essential for cellular growth and has been implicated in cell cycle control, DNA replication, and gene rearrangement found in t( 15;19)-associated carcinomas. Recently, Brd4 has been found in several transcription complexes, including the general cofactor Mediator and the P-TEFb elongation factor, and is capable of stimulating HIV-1 transcription in a Tat-independent manner. In addition, Brd4 is used as a cellular adaptor by some animal and human papillomaviruses (HPV) for anchoring viral genomes to mitotic chromosomes. This tethering, mediated by Brd4 interaction with virus-encoded E2 protein, facilitates viral genome segregation during mitosis. Interestingly, Brd4 is also identified in a transcriptional silencing complex assembled by HPVE2 and turns out to be the long sought cellular corepressor that inhibits the expression of HPV-encoded E6 and E7 oncoproteins that antagonize p53 and pRB tumor suppressor activity, respectively. The dual role of Brd4 in gene activation and repression illustrates how a dynamic chromatin-binding adaptor is able to recruit distinct transcriptional regulators to modulate promoter activity through cell cycle progression.