Other
19 Authors
- Chin A,
- Abdellatif M,
- Tang F,
- Sayed D,
- Schesing K,
- Bhat S,
- Cho J,
- Oka SI,
- Ikeda Y,
- Zhai P,
- Sadoshima J,
- Warren JS,
- Ralda G,
- Ikeda S,
- Shirakabe A,
- Tian Y,
- Byun J,
- Hsu CP,
- Babu G
| First Author | Bhat S | Year | 2019 |
| Journal | Circ Heart Fail | Volume | 12 |
| Issue | 3 | Pages | e005529 |
| PubMed ID | 30798619 | Mgi Jnum | J:292586 |
| Mgi Id | MGI:6445106 | Doi | 10.1161/CIRCHEARTFAILURE.118.005529 |
| Citation | Bhat S, et al. (2019) Recruitment of RNA Polymerase II to Metabolic Gene Promoters Is Inhibited in the Failing Heart Possibly Through PGC-1alpha (Peroxisome Proliferator-Activated Receptor-gamma Coactivator-1alpha) Dysregulation. Circ Heart Fail 12(3):e005529 |
| abstractText | BACKGROUND: Proper dynamics of RNA polymerase II, such as promoter recruitment and elongation, are essential for transcription. PGC-1alpha (peroxisome proliferator-activated receptor [PPAR]-gamma coactivator-1alpha), also termed PPARGC1a, is a transcriptional coactivator that stimulates energy metabolism, and PGC-1alpha target genes are downregulated in the failing heart. However, whether the dysregulation of polymerase II dynamics occurs in PGC-1alpha 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-1alpha target metabolic gene promoters in the pressure-overload-induced heart failure model. PGC-1alpha-cKO (cardiac-specific PGC-1alpha 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-1alpha target genes, even under basal conditions. However, the protein levels of PGC-1alpha 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-1alpha was consistently reduced both in the pressure-overload model and PGC-1alpha-cKO mice. In vitro DNA binding assays using an endogenous PGC-1alpha target gene promoter sequence confirmed that PGC-1alpha recruits polymerase II to the promoter. CONCLUSIONS: These results suggest that PGC-1alpha promotes the recruitment of polymerase II to the PGC-1alpha target gene promoters. Downregulation of PGC-1alpha target genes in the failing heart is attributed, in part, to a reduction of the PGC-1alpha occupancy and the polymerase II recruitment to the promoters, which might be a novel mechanism of metabolic perturbations in the failing heart. |
