BET Protein-Mediated Transcriptional Regulation in Heart Failure

• Published in: International journal of molecular sciences Vol. 22; no. 11; p. 6059
• Main Authors: Ijaz, Talha, Burke, Michael A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 04.06.2021; MDPI AG
• Subjects: Animals; BET; BRD4; chromatin remodeling; dilated cardiomyopathy; Gene Expression Regulation; heart failure; Heart Failure - genetics; Homeostasis; Humans; Models, Biological; Myocytes, Cardiac - metabolism; phospholamban; Review; Transcription Factors - metabolism; BET; heart failure; transcription regulation; chromatin remodeling; phospholamban; superenhancer; BRD4; dilated cardiomyopathy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22116059

Heart failure is a complex disease process with underlying aberrations in neurohormonal systems that promote dysregulated cellular signaling and gene transcription. Over the past 10 years, the advent of small-molecule inhibitors that target transcriptional machinery has demonstrated the importance of the bromodomain and extraterminal (BET) family of epigenetic reader proteins in regulating gene transcription in multiple mouse models of cardiomyopathy. BETs bind to acetylated histone tails and transcription factors to integrate disparate stress signaling networks into a defined gene expression program. Under myocardial stress, BRD4, a BET family member, is recruited to superenhancers and promoter regions of inflammatory and profibrotic genes to promote transcription elongation. Whole-transcriptome analysis of BET-dependent gene networks suggests a major role of nuclear-factor kappa b and transforming growth factor-beta in the development of cardiac fibrosis and systolic dysfunction. Recent investigations also suggest a prominent role of BRD4 in maintaining cardiomyocyte mitochondrial respiration under basal conditions. In this review, we summarize the data from preclinical heart failure studies that explore the role of BET-regulated transcriptional mechanisms and delve into landmark studies that define BET bromodomain-independent processes involved in cardiac homeostasis.