The Functions of BET Proteins in Gene Transcription of Biology and Diseases

Abstract

The BET (bromodomain and extra-terminal domain) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT, are widely acknowledged as major transcriptional regulators in biology. They are characterized by two tandem bromodomains (BDs) that bind to lysine-acetylated histones and transcription factors, recruit transcription factors and coactivators to target gene sites, and activate RNA polymerase II machinery for transcriptional elongation. Pharmacological inhibition of BET proteins with BD inhibitors has been shown as a promising therapeutic strategy for the treatment of many human diseases including cancer and inflammatory disorders. The recent advances in bromodomain protein biology have further uncovered the complex and versatile functions of BET proteins in the regulation of gene expression in chromatin. In this review article, we highlight our current understanding of BET proteins' functions in mediating protein-protein interactions required for chromatin-templated gene transcription and splicing, chromatin remodeling, DNA replication, and DNA damage repair. We further discuss context-dependent activator vs. repressor functions of individual BET proteins, isoforms, and bromodomains that may be harnessed for future development of BET bromodomain inhibitors as emerging epigenetic therapies for cancer and inflammatory disorders.

Keywords: bromodomain; bromodomain and extra-terminal domain proteins; cancer; gene transcription; inhibitors.

FIGURE 1

Functional domains of BET family proteins. Schematic representation of domain architectures for BET proteins, BRD4 long and short isoforms, BRD2, BRD3, and BRDT: BD1, first bromodomain; BD2, second bromodomain; NPS, N-terminal phosphorylation site; BID, basic residue-enriched interaction domain; ET, extra-terminal; CPS, C-terminal phosphorylation site; CTM, C-terminal motif.

FIGURE 2

Regulation of BET protein expression and functions in diseases. Expression and activity of BET proteins are regulated at different levels, including (A) transcription by 5-hydroxymethylcytosine (5-hmC) at the BRD4 promoter, (B) messenger RNA (mRNA) stability by binding of microRNA (miRNA) to the 3′ untranslated region (UTR) of BRD4 mRNA transcripts, and (C) translation by N ⁶-methyladenosine (m⁶A) modification of mRNA (Rahman et al., 2011).

FIGURE 3

Functional modulation of BET proteins by chemical modifications and protein or nucleic acid interactions. (A) Protein stability and activity by post-translational modifications such as acetylation (Ac), phosphorylation (P), ubiquitination (Ub), and proline-hydroxylation (Pro-H); (B) modulation of DNA binding through interactions with circular RNA (circRNA) and enhancer RNA (eRNA); (C) BRD4 transcriptional activity and condensate formation through interactions with long non-coding RNA (lncRNA).

FIGURE 4

Molecular functions of BET proteins in gene transcription in chromatin. Illustration of the molecular functions of BET proteins in regulation of gene transcription in chromatin, including (I) transcription factor recruitment, (II) transcription factor stability, (III) chromatin remodeling, (IV) transcriptional elongation through phosphorylation of RNA Pol-II Ser2, (V) chromatin insulator activity, (VI) super-enhancer assembly and condensates, (VII) DNA damage response and genome integrity, and (VIII) integration of gene transcription and splicing.