The role of transcription factor Ying-Yang 1 in the cardiac bioenergetics regulation

转录因子Ying-Yang 1在心脏生物能调节中的作用

• 批准号: 10688160
• 负责人: Ning Feng
• 金额: $ 7.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688160
• 关键词: Acetylation; Bioenergetics; Biogenesis; Brain-Derived Neurotrophic Factor; Cardiac; Cardiac Myocytes; Cause of Death; Data; Deacetylation; EP300 gene; Epigenetic Process; Exercise; Future; Gene Expression; Genes; Genetic Transcription; Goals; Heart; Heart failure; Histone Deacetylase; Histone Deacetylase Inhibitor; Impairment; Knockout Mice; Metabolic; Metabolic Control; Metabolism; Mitochondria; Modeling; Molecular; Nuclear; Oxidative Phosphorylation; PPAR gamma; Pathologic; Phenotype; Play; Process; Production; Proteins; Regulation; Research Personnel; Research Project Grants; Respiration; Role; Small Interfering RNA; Stress; Swimming; Testing; Transcription Coactivator; Transcription Repressor; Transcriptional Activation; Yin-Yang; aorta constriction; biological adaptation to stress; cofactor; endurance exercise; gene repression; heart cell; heart function; heart metabolism; hemodynamics; in vivo; knock-down; new therapeutic target; p300/CBP-Associated Factor; response; therapeutic target; transcription factor; transcriptional reprogramming

Project summary Pathological cardiac stress induces transcriptional reprogramming leading to maladaptive phenotypes, including metabolic impairment. A hallmark of metabolic derangement in heart failure is the suppressed expression of a network of nuclear transcription factors controlling metabolic genes transcription, including Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). PGC-1α is the master regulator of mitochondrial biogenesis and oxidative phosphorylation. On the contrast, cardiac PGC-1α expression and bioenergetics are upregulated in response to endurance exercise. To date, the mechanisms of the regulation of PGC-1α in cardiac stress response are still poorly understood. My K08 research project focused on investigating the role of Brain-derived Neurotrophic Factor (BDNF) in the regulation of cardiac energetics. We found that Yin-Yang transcription factor (YY1), a multi-functional transcription factor, plays a critical role in BDNF-induced PGC-1α expression and metabolism in cultured cardiomyocytes. However, the precise role of YY1 in cardiac bioenergetics regulation in vivo is largely unknown. Our preliminary data showed that YY1 expression was upregulated in the hearts subjected to endurance exercise as well as in failing hearts. Therefore, there is a discrepancy between YY1 and PGC-1α expression. YY1 acts as transcriptional activator and repressor depending on surrounding epigenetic proteins or transcription co-factors. It is known that acetylation of YY1 through acetyltransferase p300 leads to transcriptional activation of downstream genes, whereas deacetylation of YY1 through histone deacetylases (HDACs) leads to transcriptional repression. Our preliminary data showed that HDAC inhibition increased PGC-1α expression in heart failure. In this proposal, we will test the hypothesis that the YY1 plays an essential role in cardiac bioenergetics in cardiac stress response through PGC-1α expression regulation, and the regulation of PGC-1α expression by YY1 is determined by dynamic acetylation.

项目摘要 病理心脏应力引起转录重编程，导致 适应不良的表型，包括代谢障碍。代谢的标志 心力衰竭的进化是核网络的抑制表达 控制代谢基因转录的转录因子，包括过氧化物组 增殖物激活的受体伽马共振剂1-α（PGC-1α）。 PGC-1α是 线粒体生物发生和氧化磷酸化的主要调节剂。在 对比度，心脏PGC-1α表达和生物能学是根据 耐力运动。迄今为止，心脏PGC-1α调节的机制 压力反应仍然很少了解。我的K08研究项目的重点是 研究脑衍生的神经营养因子（BDNF）在调节中的作用 心脏能量学。我们发现阳阳的转录因子（yy1），一种多功能 转录因子，在BDNF诱导的PGC-1α表达和 培养的心肌细胞中的代谢。但是，YY1在心脏中的确切作用 体内的生物能量调节在很大程度上是未知的。我们的初步数据表明yy1 表达在接受耐力运动的心中更新 失败的心。因此，YY1和PGC-1α表达之间存在差异。 YY1充当转录激活剂和反射器，具体取决于周围的表观遗传学 蛋白质或转录辅助因子。众所周知，yy1的乙酰化 乙酰转移酶P300导致下游基因的转录激活，而 YY1通过组蛋白脱乙酰基酶（HDACS）的脱乙酰化导致转录 抑制。我们的初步数据表明HDAC抑制增加了PGC-1α 心力衰竭的表达。在此提案中，我们将检验YY1播放的假设 通过PGC-1α的心脏应激反应中心脏生物能力的重要作用 表达调控，YY1对PGC-1α表达的调节取决于 动态乙酰化。