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

项目总结 病理性心脏应激诱导转录重编程导致 不适应表型，包括代谢障碍。新陈代谢的标志 心力衰竭中的紊乱是核网络的抑制表达 控制代谢基因转录的转录因子，包括过氧化物酶体 增殖物激活受体共激活物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者。论 相反，心脏前列腺素C-1α表达和生物能量学上调 耐力锻炼。到目前为止，前列腺素C-1α在心脏中的调节机制 人们对压力的反应仍然知之甚少。我的K08研究项目专注于 脑源性神经营养因子在脑缺血再灌注损伤中的调控作用 心脏能量学。我们发现阴阳转录因子(YY1)，一种多功能的 转录因子在脑源性神经营养因子诱导的pGC-1α表达中起关键作用 培养的心肌细胞的新陈代谢。然而，YY1在心脏疾病中的确切作用 生物能量学在体内的调控在很大程度上是未知的。我们的初步数据显示，YY1 在接受耐力训练的心脏中表达上调，在 心脏衰竭。因此，YY1和PGC-1的α表达存在差异。 YY1依赖于周围的表观遗传学发挥转录激活和抑制作用 蛋白质或转录辅助因子。已知YY1的乙酰化通过 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(HDACs)脱乙酰基导致转录 压抑。我们的初步数据显示，抑制HDAC使pGC-1α增加 在心力衰竭中的表达。在这个提案中，我们将测试YY1播放的假设 心脏生物能量学通过pGC-1α在心脏应激反应中的重要作用 表达调控，而YY1对pGC-1α表达的调控是由 动态乙酰化。

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.