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

• 批准号: 10471883
• 负责人: JOSEPH A HILL
• 金额: $ 61.53万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/10471883
• 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; 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

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.

项目摘要 以及修饰符基因，序列变体，内源性因素和 环境线索，有力的证据表明表观遗传事件导致心力衰竭 发病。此外，肿瘤学已经出现了表观遗传疗法。工作 我们的实验室和其他实验室表现出了小分子抑制剂的强大心脏保护作用 在压力超负荷应力和 缺血/再灌注损伤。在此提案中，我们将把重点转移到所谓的“读者” 乙酰化，BRD蛋白，特别是BRD4。 文献中的先前工作表明，BRD蛋白的小分子抑制剂 钝病理性心脏重塑，提高了靶向这种生物学的诱人前景 为了治疗收益。在实施BRD4的研究中，特定BRD同工型的耗竭。 重要的是，BRD4通过心脏（BRD-L和BRD-S）中至少编码两个同工型 替代外显子用法。长的同工型BRD4-L在BET家族中是独特的，因为它包含 包括P-TEFB相互作用域的扩展C末端。 BRD4已知可以调节 超级角色，大量的转录增强子簇，这些增强子驱动基因表达 定义细胞身份。实际上，超增强功能需要BRD4-L，而C末端 与超增强剂群集形成的相移所需的域。这 短同工型BRD4-S缺乏此C末端。 除了这些结构上的差异之外，在肿瘤学和其他领域的背景下，很明显 这些BRD4同工型具有独特的 - 确实是对抗的功能，这一事实是 使对心血管空间中现有数据的解释变得复杂。目前，什么都没有 知道这些BRD4同工型在心脏中的作用。 我们使用心肌细胞特异性BRD4敲除鼠标的初步数据表明损失 BRD4的脑膜收缩功能和扩张心肌病的迅速下降。 我们的初步体外研究和针对特定BRD4同工型的体内研究表明 心脏肥大不需要BRD4-L，而是肥厚的反应是 取决于BRD4-S。在这里，我们提出了基于过度骑行假设的工作 BRD4的特定同工型在心肌细胞生理学和 病理。揭露同工型特异性功能将是迈向精确的重要一步 靶向疾病疗法中的生物学。我们已经开发了独特的工具来直接 评估体外和体内这些同工型的作用。