Effect of cardiomyocyte-specific activation of nuclear receptor subfamily 4 group A member 2 (NR4A2) on the regulation of gene expression in the mouse heart [ChIP-Seq]

Nuclear receptor subfamily 4 group A member 2 (NR4A2) is a widely expressed immediate early gene induced by a host of physiological signals such as growth factors, cytokines, and neurotransmitters. In the adult mammalian heart, including in cardiomyocytes, NR4A2 mRNAs increase more than 60-fold in response to beta-adrenergic stimulation. However, the identity of the genes directly regulated by NR4A2 in the stressed heart has remained poorly investigated. Using quantitative ChIP-seq data, we show here that activation of glycolysis in the mouse heart upon NR4A2 induction is directly linked to increased binding of the nuclear receptor to the promoter and enhancers of genes encoding glycolytic enzymes. Increased binding of NR4A2 to enhancers located within the imprinted Dlk1-Dio3 locus was also associated with the up-regulation of several dozen non-coding RNAs (lncRNAs and miRNAs) known for coordinating critical steps of cardiac development and for inhibiting mitochondrial function in myocytes. The findings shed light on a novel regulatory mechanism controlling cardiac homeostasis, and establish a framework to investigate further the roles played by NR4A2 in cardiac metabolic remodeling in the face of various acute and pathological stress conditions.