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.

项目概要 病理性心脏应激诱导转录重编程，导致 适应不良表型，包括代谢障碍。 心力衰竭的紊乱是核网络表达受到抑制 控制代谢基因转录的转录因子，包括过氧化物酶体 增殖剂激活受体γ共激活剂1-α（PGC-1α）是。 线粒体生物合成和氧化磷酸化的主要调节因子。 相比之下，心脏 PGC-1α 表达和生物能学响应上调 迄今为止，关于PGC-1α在心脏中的调节的耐力机制。 我的 K08 研究项目的重点是压力反应。 研究脑源性神经营养因子（BDNF）在调节中的作用 我们发现了多功能的阴阳转录因子（YY1）。 转录因子，在 BDNF 诱导的 PGC-1α 表达中起关键作用 然而，YY1 在心脏中的确切作用。 我们的初步数据表明，YY1 体内的生物能量调节在很大程度上是未知的。 在进行耐力运动的心脏中以及在 因此，YY1 和 PGC-1α 的表达存在差异。 YY1 根据周围的表观遗传充当转录激活子和阻遏子 已知 YY1 通过乙酰化。 乙酰转移酶 p300 导致下游基因的转录激活，而 YY1 通过组蛋白脱乙酰酶 (HDAC) 脱乙酰化导致转录 我们的初步数据表明 HDAC 抑制增加了 PGC-1α。 在本提案中，我们将测试 YY1 发挥作用的假设。 通过 PGC-1α 在心脏生物能量学中在心脏应激反应中发挥重要作用 YY1 对 PGC-1α 表达的调节由下式决定： 动态乙酰化。