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

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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.