BRD4

BRD4 is a member of the bromodomain and extraterminal (BET) family of chromatin readers. It recognizes acetylated lysine residues on histones and non-histone proteins, linking chromatin structure to transcriptional regulation. BRD4 plays a key role in regulating the expression of genes involved in cell growth and differentiation by modulating chromatin accessibility and recruitment of transcriptional machinery.

Structure and mechanism: BRD4 contains two bromodomains (BD1 and BD2) and a C-terminal extraterminal (ET) domain. The N-terminal region interacts with transcriptional elongation factors, including P-TEFb (CDK9/Cyclin T). BRD4 binds acetylated chromatin and helps recruit P-TEFb to promoter and enhancer regions, promoting RNA polymerase II release from promoter-proximal pausing and transcriptional elongation. BRD4 can form phase-separated condensates at super-enhancers and is involved in sustained expression of lineage-determining genes and oncogenes such as MYC.

Biological roles and disease: BRD4 regulates gene expression programs during development and in immune responses. It is implicated in cancer, where dependence on BRD4-linked transcription is exploited by therapies. A fusion of BRD4 with NUT (BRD4-NUT) drives NUT midline carcinoma by enforcing undifferentiated transcriptional programs. BRD4 activity has also been linked to inflammation and fibrosis.

Therapeutic targeting: Small-molecule inhibitors of BRD4 and other BET proteins (for example JQ1, I-BET, CPI-0610) bind the acetyl-lysine pockets in BD1/BD2, displacing BRD4 from chromatin and downregulating pro-survival genes. BET inhibitors are being evaluated in hematologic and solid tumors, often in combination regimens. Common adverse effects include cytopenias and fatigue; resistance mechanisms are under study.

Additional notes: BRD4 exists in multiple isoforms, BRD4-L and BRD4-S, and participates in various protein-protein interactions with chromatin remodelers and transcriptional coactivators.