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.

Therapeutical interference with the epigenetic landscape of germ cell tumors: a comparative drug study and new mechanistical insights

“…Moreover, based on ‘methylation-inscribed nascent transcripts sequencing’ (MINT-seq), N 6 -methyladenosine (m 6 A)-marked enhancer RNAs (eRNAs) have been identified to recruit the nuclear m 6 A reader YTHDC1, resulting in the formation of m 6 A-eRNA/YTHDC1 condensates, which promote BRD4 /BRD4 co-activator formation [ 40 ]. Further, Cheung et al summarized that the expression and activity of BRD4 was further regulated by miRNA binding to the 3′ UTR of BRD4 , as well as post-translationally by acetylation, phosphorylation, ubiquitination and proline hydroxylation [ 41 ]. Additionally, we validated high BRD4 and EZH2 levels by western blotting in four different GCT cell lines (Additional file 1 : Fig.…”

Zebrafish Paralogs brd2a and brd2b Are Needed for Proper Circulatory, Excretory and Central Nervous System Formation and Act as Genetic Antagonists during Development

“…Prestaining of blots for total protein ( Figure 2 B,D) shows that lack of signal on blot in C is due to peptide competition during antibody incubation and not due to lack of protein loading. It is possible that the band at >150 kD represents full-length Brd2b-L (predicted MW 91 kD), where differences from the predicted might be due to post-translational modification and/or stable complex formation [ 42 ]. In any case, the putative full-length protein is found in both ovaries/oocytes and embryos, while the smaller product is most prominently found in later stage embryos.…”

JQ-1 ameliorates schistosomiasis liver granuloma in mice by suppressing male and female reproductive systems and egg development of Schistosoma japonicum

“…Bromodomains that specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code. BET proteins play a crucial role in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones during cell proliferation and differentiation [10-11]. Brd2 mRNA is express in distinct patterns during ovarian folliculogenesis, which is essential for embryonic development in the mouse [12-13], Brdt acetylated histone H4-dependent chromatin remodeling in mammalian spermiogenesis is essential for male germ cell differentiation [14-15].…”