Bromodomain 4: a cellular Swiss army knife

Abstract

Bromodomain protein 4 (BRD4) is a transcriptional and epigenetic regulator that plays a pivotal role in cancer and inflammatory diseases. BRD4 binds and stays associated with chromatin during mitosis, bookmarking early G1 genes and reactivating transcription after mitotic silencing. BRD4 plays an important role in transcription, both as a passive scaffold via its recruitment of vital transcription factors and as an active kinase that phosphorylates RNA polymerase II, directly and indirectly regulating transcription. Through its HAT activity, BRD4 contributes to the maintenance of chromatin structure and nucleosome clearance. This review summarizes the known functions of BRD4 and proposes a model in which BRD4 actively coordinates chromatin structure and transcription.

Keywords: BRD4; Pol II; acetyltransferase; kinase; nucleosome eviction.

Figure 1.. Functional domains on mouse and human BRD4.

Numbers on cartoon indicate amino acid boundaries of known BRD4 domains. BID, basic residue–enriched interaction domain, CPS, C terminal cluster of phosphorylation sites, NPS, N terminal cluster of phosphorylation sites.

Figure 2.. Model incorporating BRD4 molecular functions and the proposed sequence in which its enzymatic activities function.

BRD4 binds to mitotic chromatin, bookmarking early G1 genes. Toward the end of mitosis, BRD4 acetylates histones, initially on the tail lysines and eventually on H3K122 in the globular region of histone H3, which leads to nucleosome clearance and enables the recruitment of transcription machinery. BRD4 then regulates transcriptional pause release and elongation via its phosphorylation of RNA Pol II CTD and its recruitment of PTEFb to the preinitiation complex containing transcription factor II H (TFIIH).