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Cardiomyocyte bromodomain protein 4 (BRD4) in physiology and disease

心肌细胞溴结构域蛋白 4 (BRD4) 在生理学和疾病中的作用

基本信息

批准号：
10241315
负责人：
JOSEPH A HILL
金额：
$ 61.98万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241315
关键词：
Acetylation Biology Bromodomain C-terminal Cardiac Cardiac Myocytes Cardiac development Cardiovascular system Cells ChIP-seq Chromatin Chromatin Structure Clinical Coupled Cues Data Dilated Cardiomyopathy Disease Endogenous Factors Engineering Enhancers Epigenetic Process Event Exons Family Family member Fostering Gene Expression Gene Expression Profile Genes Genetic Transcription Growth HDAC1 gene Heart Heart Hypertrophy Heart failure Homeostasis In Vitro Knockout Mice Literature Mitochondria Oncology Outcome Pathogenesis Pathologic Pathology Pathway interactions Phase Phenotype Physiology Play Positive Transcriptional Elongation Factor B Post-Translational Protein Processing Process Protein Family Protein Isoforms Proteins RNA Interference Reader Reperfusion Injury Role Small Interfering RNA Stress Structure Therapeutic Transcription Alteration Transcriptional Regulation Transgenic Mice Variant Ventricular Work base cardioprotection epigenetic therapy heart function histone modification in vitro Model in vivo interest knock-down knockout animal mouse model pressure response small molecule small molecule inhibitor tool transcriptome sequencing

项目摘要

Project Summary Together with the effects of modifier genes, sequence variants, endogenous factors, and environmental cues, strong evidence points to epigenetic events contributing to heart failure pathogenesis. Furthermore, epigenetic therapies have emerged already in oncology. Work from our lab and others has demonstrated robust cardioprotective effects of small molecule inhibitors of class 1 histone deacetylases (acetyl “erasers”) in both pressure-overload stress and ischemia/reperfusion injury. In this proposal, we will turn our focus to the so-called “readers“ of acetylation, the BRD proteins, specifically BRD4. Prior work in the literature has demonstrated that a small molecule inhibitor of BRD proteins blunts pathological cardiac remodeling, raising the tantalizing prospect of targeting this biology for therapeutic gain. Depletion of specific BRD isoforms in those studies implicated BRD4. Importantly, BRD4 encodes at least two isoforms in the heart (BRD-L and BRD-S) via alternative exon usage. The long isoform BRD4-L is unique in the BET family in that it contains an extended C terminus that includes a P-TEFb-interacting domain. BRD4 is known to regulate superenhancers, large clusters of transcriptional enhancers that drive expression of genes that define cell identity. Indeed, BRD4-L is required for super-enhancer function, with the C-terminal domain necessary for the phase-shift occurring with formation of super-enhancer clusters. The short isoform BRD4-S lacks this C terminus. Beyond these structural differences, it is clear in the context of oncology and other domains that these BRD4 isoforms have distinct – indeed antagonistic – functions, a fact which complicates the interpretation of existing data in the cardiovascular space. Presently, nothing is known about the role of these BRD4 isoforms in the heart. Our preliminary data, using a cardiomyocyte-specific BRD4 knockout mouse, show that loss of BRD4 results in a rapid decline in ventricular contractile function and dilated cardiomyopathy. Our preliminary in vitro studies and in vivo studies targeting specific BRD4 isoforms suggests that BRD4-L is not required for cardiac hypertrophy, but rather, the hypertrophic response is dependent on BRD4-S. Here, we propose work based on the over-riding hypothesis that specific isoforms of BRD4 play distinct roles in cardiomyocyte physiology and pathology. Work to unveil isoform-specific functions will be a major step toward precision targeting of this biology in disease therapy. Already, we have developed unique tools to directly assess the roles of these isoforms both in vitro and in vivo.

项目总结