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 manner dependent on tissue type and developmental stage. However, its role in cardiac energetic regulation remains unclear. We found that cardiac-specific YY1 knockout (cYY1 KO) mice exhibited cardiac dysfunction after 2 wk of swimming exercise, suggesting an impaired adaptive cardiac response. Further analysis revealed that exercise-induced upregulation of transcription factor networks governing cardiac metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), was blunted in cYY1 KO mice. Correspondingly, citrate synthase activity, a marker of mitochondrial content, was reduced in these mice. Under transaortic constriction (TAC), cYY1 KO mice developed significantly exacerbated heart failure. RNA sequencing revealed downregulation of metabolic genes and pathways, including PGC-1α, in the hearts of TAC cYY1 KO mice. In addition, mitochondrial complex protein levels and complexes I and IV activities 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. p300 activates PGC-1α transcription in the heart, whereas HDAC3 suppresses PGC-1α transcription. These findings suggest that YY1-mediated transcriptional regulation of metabolic genes is modulated by the epigenetic regulators p300 and HDAC3. The interaction between YY1 and either p300 or HDAC3 may underlie the differences in cardiac energy regulation observed during exercise compared with pathological stress.<b>NEW & NOTEWORTHY</b> We are the first to demonstrate that YY1 is essential for cardiac energetic regulation using a cardiac-specific YY1 KO mouse model. Furthermore, we discovered that YY1's regulation of metabolic gene transcription is modulated by the epigenetic proteins p300 and HDAC. This mechanism may contribute to the differences in cardiac energetic regulation in response to exercise versus pathological stress.