The SRCAP chromatin remodeling complex promotes oxidative metabolism during prenatal heart development

Mammalian heart development relies hugely on cardiomyocyte mitochondrial maturation and metabolism. Embryonic cardiomyocytes make metabolic shift from anaerobic glycolysis to oxidative metabolism by mid-gestation. The VHL-HIF signaling favors anaerobic glycolysis but this process subsides by E14.5. Meanwhile, the oxidative metabolism becomes activated but its regulation is largely elusive. Here, we first pinpointed a critical temporal window for mitochondrial maturation and metabolic shift, and uncovered the pivotal role of the SRCAP chromatin remodeling complex in these processes. Disruption of this complex massively suppressed the transcription of key genes required for the tricarboxylic acid (TCA) cycle, fatty acid β-oxidation and ubiquinone biosynthesis, and destroyed respirasome stability. Furthermore, we found that the SRCAP complex functioned through H2A.Z deposition to activate transcription of metabolic genes. These findings unveiled the important physiological functions of SRCAP complex in regulating mitochondrial maturation and promoting oxidative metabolism during heart development, and shed new light on the transcriptional regulation of ubiquinone biosynthesis.