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brd4

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Official Full Name
bromodomain containing 4
Background
The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human 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 an upper respiratory tract carcinoma in young people. Two alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]
Synonyms
BRD4; bromodomain containing 4; CAP; MCAP; HUNK1; HUNKI; bromodomain-containing protein 4; bromodomain-containing 4; chromosome-associated protein; PGLS; 6-phosphogluconolactonase; fb18g03; wu:fb18g03; bromodomain 4

Bromodomain-containing protein 4 (BRD4) is a member of the bromodomain and extraterminal (BET) family proteins, it has two N-terminal brominedomains and one extraterminal (ET) domain. BRD4 binds to acetylated histones and transcription factors through the bromodomain and recruit transcriptional regulators such as positive transcription elongation factor b (P-TEFb) and Mediator complex. BRD4 is engaged in the activation of genes involved in cell growth and cell cycle progression. BRD4 was identified originally as a ubiquitously expressed chromatin adapter that maintains epigenetic memory and regulates cell cycle progression. Recently, it was considered a key determinant in acute myeloid leukemia, multiple myeloma, Burkitt’s lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease.

Chromatin-reading proteins that recognize and bind acetylated histones play a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Productive transcription is dependent on the phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II (Pol II). Phosphorylation of the CTD residues serine 5 and serine 2 is necessary for the recruitment of RNA capping and splicing factors, respectively. CTD serine 5 residues are phosphorylated primarily by the CDK7 kinase component of TFIIH. Devaiah et al. has shown that BRD4 is an atypical kinase that binds to and phosphorylates the Pol II CTD serine 2 in vitro and in vivo. And currently attribution of serine 2’s phosphorylation is the CDK9 subunit of PTEFb and/or CDK12/13. P-TEFb nuclear localization and activation depends on BRD4, which is required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P-TEFb, which translates it into active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II. We can know for sure that BRD4 was directly or indirectly involved phosphorylation of the CTD residues serine 2.

Autophagy is a membrane transport process that directs the degradation of cytoplasmic substances in lysosome. This process promotes cell fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. BRD4 participates in the activation of genes involved in cell growth and cell cycle progression. Sakamaki et al. has shown that BRD4 suppresses the expression of a subset of autophagy and lysosome genes by binding to the promoter regions under normal growth conditions and that this repression is alleviated in response to certain autophagic stimuli. Inhibition of BRD4 enhances autophagic flow and lysosome function, which consequently Promotes degradation of pathogenic protein aggregates and confers resistance to starvation-induced cell death. These observations therefore provide important insights into a regulatory mechanism controlling autophagy and lysosome function.

Fig 1. Bromodomain protein BRD4 is a transcriptional repressor of autophagy and lysosomal function. (Sakamaki et al., 2017, Molecular Cell 66, 517–532).

Devaiah et al. demonstrated that BRD4 has a different intrinsic HAT activity than other known acetyltransferases. BRD4 acetylates lysines on the tails of H3 and H4 and, importantly, on H3K122, lysine residues located in the globular domain of histone octamer with the strongest histone-DNA interaction. BRD4 colocalizes with H3K122ac genome-wide and its acetylation of H3 leads to nucleosomal disassembly and nuclear expansion, consistent with chromatin de-compaction. BRD4 preferentially reduces nucleosome occupancy around genes it is known to bind to and regulate such as MYC, FOS and AURKB. In addition, conditional deletion of BRD4 in thymus results in decreased H3K122ac levels and perturbations in thymic development. Thus, BRD4 is a chromatin active remodeling agent and active transcription regulator. Nucleosome assembly and Chromatin depolymerization mediated by BRD4 HAT activity occur preferentially at its target loci and at sites where BRD4 binds and where H3K122ac is enriched. While BRD4 de-compacted chromatin at its known targets such as MYC, FOS and AURKB genes, it does not significantly affect the nucleosome occupancy around the AURKA gene which it does not regulate. A previously reported >95% correlation between BRD4 occupancy and DNaseI hypersensitivity (DHS) sites genome-wide is consistent with our conclusion that BRD4 clears nucleosomes at its target gene loci.

The discovery of the disintegration of chromatin by BRD4 HAT activity resolves the apparent contradiction in the literature. It was reported that a truncated isoform of BRD4 insulates chromatin from de-compaction, which lacks the HAT catalytic domain, is a competitive inhibitor of full-length BRD4 that has HAT activity. Accordingly, overexpression of the truncated BRD4 isoform, containing only the N-terminal bromodomains, resulted in the aggregation of chromatin into highly compact regions. However, depletion of BRD4 resulted in increased MNase sensitivity, leading that BRD4 is necessary for higher-order chromatin structure. That this effect was not due to BRD4-mediated compaction but rather to chromothripsis induced either by premature chromosome condensation or inability to de-condense. In other words, BRD4 overexpression and depletion both lead to altered chromatin structures, but mediated by different causes. BRD4 has inherent HAT activity, which regulates chromatin remodeling, leads to the conclusion that BRD4 actively links chromatin remodeling and transcription and to the following model (Fig. 2).

Fig 2. Model for the role of BRD4 histone acetyltransferase activity. (Devaiah et al. Nat Struct Mol Biol. 2016 June.)

References:

  1. Devaiah BN, Lewis BA, Cherman N, et al. BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA Polymerase II carboxy-terminal domain. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(18):6927-6932.
  2. Sakamaki J, Wilkinson S, Hahn M, et al. Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function. Molecular Cell. 2017;66(4):517-532.e9.
  3. Hu X, Dong S-H, Chen J, et al. Prolyl isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4. Oncogene. 2017;36(36):5177-5188.
  4. Tian B, Yang J, Zhao Y, et al. BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection. Ross SR, ed. Journal of Virology. 2017;91(6): e00007-17.
  5. Devaiah BN, Case-Borden C, Gegonne A, et al. BRD4 is a Histone Acetyltransferase that Evicts Nucleosomes from Chromatin. Nature structural & molecular biology. 2016;23(6):540-548.