Zhang Manling, Peng Zishan, Ping Haiqin, Li Zoe, Liu Jia-Jun, Liu Silvia, Feng Ning
Division of Cardiology, Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
Division of Cardiology, Veteran Affair Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, United States.
Am J Physiol Heart Circ Physiol. 2025 Oct 1;329(4):H899-H906. doi: 10.1152/ajpheart.00419.2025. Epub 2025 Aug 13.
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. 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.
多效转录因子阴阳1（YY1）以依赖于组织类型和发育阶段的方式调节细胞代谢。然而，其在心脏能量调节中的作用仍不清楚。我们发现，心脏特异性YY1基因敲除（cYY1 KO）小鼠在游泳运动2周后出现心脏功能障碍，提示适应性心脏反应受损。进一步分析表明，在cYY1 KO小鼠中，运动诱导的调控心脏代谢的转录因子网络（包括过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α））的上调受到抑制。相应地，这些小鼠中线粒体含量的标志物柠檬酸合酶活性降低。在经主动脉缩窄（TAC）处理后，cYY1 KO小鼠发生明显加重的心力衰竭。RNA测序显示，TAC处理的cYY1 KO小鼠心脏中代谢基因和途径（包括PGC-1α）下调。此外，线粒体复合物蛋白水平以及复合物I和IV的活性降低，这与代谢基因转录受抑制一致。此前，我们观察到在运动和TAC处理的心脏中YY1表达增加。然而，虽然运动可增强心脏代谢，但TAC处理则损害心脏代谢。我们发现，运动期间p300与YY1的结合增加，而在TAC处理的心脏中组蛋白脱乙酰酶3（HDAC3）与YY1的结合增加。p300可激活心脏中PGC-1α的转录，而HDAC3则抑制PGC-1α的转录。这些发现表明，YY1介导的代谢基因转录调控受到表观遗传调节因子p300和HDAC3的调节。与病理应激相比，运动期间观察到的心脏能量调节差异可能是YY1与p300或HDAC3之间相互作用的结果。我们首次使用心脏特异性YY1 KO小鼠模型证明YY1对心脏能量调节至关重要。此外，我们发现YY1对代谢基因转录的调控受到表观遗传蛋白p300和HDAC的调节。这种机制可能导致运动与病理应激反应中心脏能量调节的差异。
