BET Epigenetic Reader Proteins in Cardiovascular Transcriptional Programs

Abstract

Epigenetic mechanisms involve the placing (writing) or removal (erasing) of histone modifications that allow heterochromatin to transition to the open, activated euchromatin state necessary for transcription. A third, less studied epigenetic pathway involves the reading of these specific histone marks once placed. The BETs (bromodomain and extraterminal-containing protein family), which includes BRD2, BRD3, and BRD4 and the testis-restricted BRDT, are epigenetic reader proteins that bind to specific acetylated lysine residues on histone tails where they facilitate the assembly of transcription complexes including transcription factors and transcriptional machinery like RNA Polymerase II. As reviewed here, considerable recent data establishes BETs as novel determinants of induced transcriptional programs in vascular cells, like endothelial cells and vascular smooth muscle cells, cardiac myocytes and inflammatory cells, like monocyte/macrophages, cellular settings where these epigenetic reader proteins couple proximal stimuli to chromatin, acting at super-enhancer regulatory regions to direct gene expression. BET inhibition, including the use of specific chemical BET inhibitors like JQ-1, has many reported effects in vivo in the cardiovascular setting, like decreasing atherosclerosis, angiogenesis, intimal hyperplasia, pulmonary arterial hypertension, and cardiac hypertrophy. At the same time, data in endothelial cells, adipocytes, and elsewhere suggest BETs also help regulate gene expression under basal conditions. Studies in the cardiovascular setting have highlighted BET action as a means of controlling gene expression in differentiation, cell identity, and cell state transitions, whether physiological or pathological, adaptive, or maladaptive. While distinct BET inhibitors are being pursued as therapies in oncology, a large prospective clinical cardiovascular outcome study investigating the BET inhibitor RVX-208 (now called apabetalone) has already been completed. Independent of this specific agent and this one trial or the numerous unanswered questions that remain, BETs have emerged as novel epigenetic players involved in the execution of coordinated transcriptional programs in cardiovascular health and disease.

BRD2 regulation of sigma-2 receptor upon cholesterol deprivation

“…From a functional/structural perspective, BRD4 is dubbed a "Swiss army knife" (30). Its two bromodomains "dock" the BRD4-organized regulatory complex (including TFs and cis-regulators) to specific bookmarked chromatin sites, with its C-terminal domain promoting transcriptional activation by interacting with the transcription elongation factor that in turn activates the RNA polymerase II (31). BRD4 was very recently found to possess intrinsic kinase (32) and acetyl transferase activities (33).…”

“…Inasmuch as BRD2 lacks a C-terminal domain and its bromodomain sequences are different from that of BRD4 (20), our results may implicate a BET mechanism distinct from that of BRD4. Given limited information about BRD2 functional mechanisms (31), future studies are needed to elucidate the molecular workings that underlie BRD2dominated regulation of S2R transcription.…”

Histone Deacetylases (HDACs) and Atherosclerosis: A Mechanistic and Pharmacological Review

“…Intriguingly, the BRD4 inhibitor RVX-208 (now called apabetalone) showed potent effect in increasing apolipoprotein A-I and HDL levels/particles and reducing AS (McLure et al, 2013;Jahagirdar et al, 2014;Gilham et al, 2016;Ghosh et al, 2017), and has been tested in clinical trials (Nicholls et al, 2016(Nicholls et al, , 2018Shishikura et al, 2019). Pooling completed phase 2 trial data that suggested its clinical benefits on reducing major adverse cardiovascular events in treated patients (Borck et al, 2020). However, a phase III trial (BETonMACE) completed recently showed that addition of RVX 208 to contemporary standard of care for acute coronary syndrome (ACS) did not significantly reduce major adverse cardiovascular events in patients with a recent (7-90 days) ACS, type 2 diabetes, and low HDL cholesterol (Ray et al, 2020).…”

Partnership between epigenetic reader BRD4 and transcription factor CEBPD

“…Therefore, in the pursuit of new interventional paradigms, it is important to interpret the IH pathogenic mechanisms from an epigenetic perspective. However, epigenetic determinants of SMC state transitions only begin to be unveiled 2,3 .…”

“…This action involves multiple factors such as the elongation factor complex and central machinery of transcription. It remains poorly understood how BRD4, a seeming global regulator, assumes its functional specificity in different cell types and microenvironments 2 . Transcription factors (TFs) and enhancers are thought to confer BRD4 some gene loci specificity in the genomic landscape 6,7 .…”