BRD4
Description
The BRD4 (bromodomain containing 4) is a protein-coding gene located on chromosome 19.
Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene. BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT. BRD4, similar to other BET family members, contains two bromodomains that recognize acetylated lysine residues. BRD4 also has an extended C-terminal domain with little sequence homology to other BET family members. The two bromodomains in BRD4, termed BD1 and BD2, consist of 4 alpha-helices linked by 2 loops. The ET domain structure is made up of 3 alpha-helices and a loop. The C-terminal domain of BRD4 has been implicated in promoting gene transcription through interaction with the transcription elongation factor P-TEFb and RNA polymerase II. The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human BRD2 (RING3) protein, a serine/threonine kinase. Each of these proteins contains two bromodomains, a conserved sequence motif which may be involved in chromatin targeting. This gene has been implicated as the chromosome 19 target of translocation t(15;19)(q13;p13.1), which defines the NUT midline carcinoma. Two alternatively spliced transcript variants have been described. Most cases of NUT midline carcinoma involve translocation of the BRD4 gene with NUT genes.
BRD4 is a chromatin reader protein that recognizes and binds acetylated histones, playing a key role in the transmission of epigenetic memory across cell divisions and transcription regulation. It remains associated with acetylated chromatin throughout the cell cycle, preserving acetylated chromatin status and maintaining high-order chromatin structure, which provides epigenetic memory for postmitotic G1 gene transcription. During interphase, BRD4 regulates the transcription of signal-inducible genes by associating with the P-TEFb complex and recruiting it to promoters. BRD4 also recruits P-TEFb complex to distal enhancers, so called anti-pause enhancers, in collaboration with JMJD6. BRD4 and JMJD6 are required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P-TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II. BRD4 regulates differentiation of naive CD4(+) T-cells into T-helper Th17 by promoting recruitment of P-TEFb to promoters. It promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II. A report suggests that BRD4 directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; however, these data require additional in vivo evidence. In addition to acetylated histones, BRD4 also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B. BRD4 also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, it is recruited to p53/TP53 specific target promoters.
BRD4 is also known as CAP, CDLS6, FSHRG4, HUNK1, HUNKI, MCAP.
