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: 10504503
• 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/10504503
• 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; 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; Yang; Yin-Yang; biological adaptation to stress; constriction; 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 病理性心脏应激诱导转录重编程， 适应不良表型，包括代谢障碍。新陈代谢的标志 心力衰竭的紊乱是一种核网络的表达受到抑制， 控制代谢基因转录的转录因子，包括过氧化物酶体 增殖物激活受体γ辅激活因子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。上 相比之下，心脏PGC-1α表达和生物能量学响应于 耐力训练迄今为止，PGC-1α在心肌细胞中的调节机制尚不清楚， 对应激反应仍然知之甚少。我的K 08研究项目集中在 研究脑源性神经营养因子（BDNF）在调节 心脏能量学我们发现，阴阳转录因子（YY 1），一个多功能的 转录因子，在BDNF诱导的PGC-1α表达中起关键作用， 在培养的心肌细胞中的代谢。然而，YY 1在心脏中的确切作用是不确定的。 体内生物能量学调节在很大程度上是未知的。我们的初步数据显示， 在进行耐力运动的心脏中表达上调， 心脏衰竭因此，YY 1和PGC-1α的表达存在差异。 YY 1作为转录激活因子和抑制因子，依赖于周围的表观遗传 蛋白质或转录辅因子。已知YY 1的乙酰化通过 乙酰转移酶p300导致下游基因的转录激活，而 YY 1通过组蛋白脱乙酰酶（HDAC）的脱乙酰化导致转录水平的降低。 镇压我们的初步数据表明，HDAC抑制增加PGC-1α， 心力衰竭的表现。在这个提议中，我们将测试YY 1扮演的角色的假设， 通过PGC-1α在心脏应激反应中的心脏生物能量学中的重要作用 表达调控，YY 1对PGC-1α表达的调控由以下决定： 动态乙酰化