Fig. 1. Transcriptional activation of oncogenes by BRD4.

Under physiological conditions, proliferation and survival genes are transcribed at a basal rate to maintain homoeostasis. During the transformation of normal epithelium to neoplasia or, similarly, during the progression of a primary tumour to a more invasive stage, chromatin surrounding proto-oncogenes becomes enriched for histone acetylation, especially at enhancer regions. This change in chromatin programming allows nucleosome decompaction, which facilitates the recruitment of bromodomain chromatin remodellers, such as the SWI/SNF complex, that further open chromatin to allow the binding of transcription factors (TF). Acetylation also facilitates the recruitment of bromodomain-carrying coactivators, such as BRD4. BRD4 potently activates transcription through the recruitment of the Mediator complex, which connects enhancer elements with the RNA POLII complex at the promoter region of proto-oncogenes. Mediator, through association with CDK9, a component of the p-TEFb elongation complex, phosphorylates RNA POL II on serine 2 of its C-terminal domain, thereby stimulating transcriptional elongation.