Transcription Factor Yin-Yang 1 governs cardiac metabolic reprogramming in response to exercise or pathological stress

The pleiotropic transcription factor Yin Yang 1 (YY1) regulates cellular metabolism in a stage- and tissue-dependent manner. However, its role in cardiac energetic regulation remains unclear. We found that cardiac-specific YY1 knockout (cYY1 KO) mice exhibited cardiac dysfunction after two weeks of swimming exercise, suggesting an impaired adaptive cardiac response. Further analysis revealed that exercise-induced upregulation of transcription factor networks controlling cardiac metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), was blunted in cYY1 KO mice. Consistently, citrate synthase activity, an indicator of mitochondrial content, was reduced in these mice. In response to transaortic constriction (TAC), cYY1 KO mice developed significantly exacerbated heart failure. RNA sequencing showed downregulation of metabolic genes and pathways, including PGC-1α, in TAC cYY1 KO mice hearts. Additionally, mitochondrial complex protein levels and complex I activity were reduced, consistent with suppressed metabolic gene transcription. Previously, we observed increased YY1 expression in hearts subjected to both exercise and TAC. However, while cardiac metabolism was enhanced with exercise, it was impaired with TAC. We found that p300 binding to YY1 increased during exercise, whereas histone deacetylase 3 (HDAC3) binding to YY1 increased in TAC hearts. These findings suggest that YY1-mediated transcriptional regulation of metabolic genes is modulated by the epigenetic regulators p300 and HDAC3.