Recruitment of RNA Polymerase II to Metabolic Gene Promoters Is Inhibited in the Failing Heart Possibly Through PGC-1α ( Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α) Dysregulation

BACKGROUND: Proper dynamics of RNA polymerase II, such as promoter recruitment and elongation, are essential for transcription. PGC-1 alpha (peroxisome proliferator-activated receptor [PPAR]-gamma coactivator-1 alpha), also termed PPARGC1 alpha, is a transcriptional coactivator that stimulates energy metabolism, and PGC-1 alpha target genes are downregulated in the failing heart. However, whether the dysregulation of polymerase II dynamics occurs in PGC-1 alpha target genes in heart failure has not been defined. METHODS AND RESULTS: Chromatin immunoprecipitation-sequencing revealed that reduced promoter occupancy was a major form of polymerase II dysregulation on PGC-1 alpha target metabolic gene promoters in the pressure-overload-induced heart failure model. PGC-1 alpha-cKO (cardiac-specific PGC-1 alpha knockout) mice showed phenotypic similarity to the pressure-overload-induced heart failure model in wild-type mice, such as contractile dysfunction and downregulation of PGC-1 alpha target genes, even under basal conditions. However, the protein levels of PGC-1 alpha were neither changed in the pressure-overload model nor in human failing hearts. Chromatin immunoprecipitation assays revealed that the promoter occupancy of polymerase II and PGC-1 alpha was consistently reduced both in the pressure-overload model and PGC-1 alpha-cKO mice. In vitro DNA binding assays using an endogenous PGC-1 alpha target gene promoter sequence confirmed that PGC-1 alpha recruits polymerase II to the promoter. CONCLUSIONS: These results suggest that PGC-1 alpha promotes the recruitment of polymerase II to the PGC-1 alpha target gene promoters. Downregulation of PGC-1 alpha target genes in the failing heart is attributed, in part, to a reduction of the PGC-1 alpha occupancy and the polymerase II recruitment to the promoters, which might be a novel mechanism of metabolic perturbations in the failing heart.