A Comprehensive Review of BET Protein Biochemistry, Physiology, and Pathological Roles

Abstract

Epigenetic modifications, specifically acetylation of histone plays a decisive role in gene regulation and transcription of normal cellular mechanisms and pathological conditions. The bromodomain and extraterminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT), being epigenetic readers, ligate to acetylated regions of histone and synchronize gene transcription. BET proteins are crucial for normal cellular processing as they control cell cycle progression, neurogenesis, differentiation, and maturation of erythroids and spermatogenesis, etc. Research-based evidence indicated that BET proteins (mainly BRD4) are associated with numeral pathological ailments, including cancer, inflammation, infections, renal diseases, and cardiac diseases. To counter the BET protein-related pathological conditions, there are some BET inhibitors developed and also under development. BET proteins are a topic of most research nowadays. This review, provides an ephemeral but comprehensive knowledge about BET proteins’ basic structure, biochemistry, physiological roles, and pathological conditions in which the role of BETs have been proven. This review also highlights the current and future approaches to pledge BET protein-related pathologies.

Bromodomain and Extra-Terminal Proteins in Brain Physiology and Pathology: BET-ing on Epigenetic Regulation

“…Healthy brain functioning requires fine control of gene expression in neural cells. Epigenetic regulatory mechanisms and chromatin remodeling are also crucial for cognitive functions such as learning and memory, which involve specific gene expression profiles that are necessary to ensure neural connectivity and plasticity [ 85 , 86 ].…”

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

“…There are four mammalian conserved members of BET proteins, which include BRD containing 2 (Brd2), Brd3, Brd4, and Brdt [ 5 ]. While Brdt is predominantly expressed in germ cells, Brd2, 3, and 4 are ubiquitously expressed in various tissues [ 5 ].…”

“…As histone lysine acetylation is generally associated with transcription activation, dysregulation of histone acetylation usually leads to the aberrant expression of oncogenes and subsequently promotes cancer development [ 4 ]. There are three types of proteins regulating histone acetylation, which include bromodomain (BRD) proteins [ 5 , 6 ], histone acetyltransferases [ 7 ], histone deacetylases [ 8 ], and sirtuins [ 9 ]. Acetyltransferases, BRDs, and deacetylases and sirtuins, are considered the “writers”, “readers”, and “erasers” of histone acetylation, respectively [ 10 ].…”

Attenuating iPSC reprogramming stress with dominant-negative BET peptides

“… 21 The mammalian BET family includes four members and three of them (BRD2, BRD3, and BRD4) are expressed ubiquitously. BET proteins regulate many cellular processes 21 , 22 including stress responses. 23 , 24 , 25 , 26 , 27 , 28 Mouse BRD4 was reported to promote murine iPSC reprogramming, 29 but inhibition of BET proteins promotes mouse neuron reprogramming.…”