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

Abstract

Background: Proper dynamics of RNA polymerase II, such as promoter recruitment and elongation, are essential for transcription. PGC-1α (peroxisome proliferator-activated receptor [PPAR]-γ coactivator-1α), also termed PPARGC1a, is a transcriptional coactivator that stimulates energy metabolism, and PGC-1α target genes are downregulated in the failing heart. However, whether the dysregulation of polymerase II dynamics occurs in PGC-1α 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-1α target metabolic gene promoters in the pressure-overload–induced heart failure model. PGC-1α-cKO (cardiac-specific PGC-1α 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-1α target genes, even under basal conditions. However, the protein levels of PGC-1α 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-1α was consistently reduced both in the pressure-overload model and PGC-1α-cKO mice. In vitro DNA binding assays using an endogenous PGC-1α target gene promoter sequence confirmed that PGC-1α recruits polymerase II to the promoter. Conclusions: These results suggest that PGC-1α promotes the recruitment of polymerase II to the PGC-1α target gene promoters. Downregulation of PGC-1α target genes in the failing heart is attributed, in part, to a reduction of the PGC-1α occupancy and the polymerase II recruitment to the promoters, which might be a novel mechanism of metabolic perturbations in the failing heart.

Multiple Levels of PGC-1α Dysregulation in Heart Failure

“…Some reports have suggested that downregulation of PGC-1α is a major cause of mitochondrial impairment and metabolic defects in the failing heart (7,8,21,22). However, other studies, including ours, suggest that the expression levels of PGC-1α per se cannot always explain downregulation of PGC-1α target genes in the failing heart (23)(24)(25). In this review, we carefully analyze recent findings in an attempt to construct a holistic picture of the complex mechanisms contributing to impaired PGC-1α regulatory function in the failing heart.…”

“…However, the dynamics of PGC-1α expression in the failing heart may be more complex. In animal models of failure, most of the studies showed downregulation of PGC-1α (8,(51)(52)(53)(54)(55)(56)(57), but some studies found no change (24,25,58). Likewise, analysis of tissue samples obtained from patients at the advanced stage of heart failure showed a variability of outcomes, including decreased gene (59) or protein (60) expression, unchanged gene expression (61,62), or even a slightly increased gene expression of PGC-1α (63).…”

“…(C) PGC-1α's transcriptional control of metabolic genes (i.e., Acadm, Sdha, Idh3a) largely depends on interaction with DNA-binding transcriptional factors (TF) [i.e., ERRs, PPARs, reviewed in (36)]. In addition, our recent study showed that PGC-1α recruits RNA Polymerase II (RNA PolII) to the promoter regions of PGC-1α target genes (25). Moreover, PGC-1α is dissociated from the promoters of its target genes and RNA PolII in the failing mouse heart (25).…”

“…In addition, our recent study showed that PGC-1α recruits RNA Polymerase II (RNA PolII) to the promoter regions of PGC-1α target genes (25). Moreover, PGC-1α is dissociated from the promoters of its target genes and RNA PolII in the failing mouse heart (25). We propose that this alteration of PGC-1α behavior in the failing heart is secondary to a PTM of the PGC-1α protein, and intend to test this hypothesis in our future studies.…”

“…Despite the phenotypic variation in these two lines of global PGC-1α knockout mice, hemodynamic challenge in the form of transverse aortic banding consistently led to pronounced cardiac failure in PGC-1α null mice (8,53). To further investigate the role of cardiac PGC-1α, three independent groups, including us, have generated cardiac-specific PGC-1α knockout line with identical PGC-1α flox and αMHC-Cre lines (25,71,72). The Tavi group and we observed the similar degree of cardiac dysfunction in cardiac-specific PGC-1α knockout mice under basal conditions (25,72).…”