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

Santosh Bhat, Adave Chin, Akihiro Shirakabe, Yoshiyuki Ikeda, Shohei Ikeda, Peiyong Zhai, Chiao Po Hsu, Danish Sayed, Maha Abdellatif, Jaemin Byun, Kevin Schesing, Fan Tang, Yimin Tian, Gopal Babu, Guersom Ralda, Junco S. Warren, Jaeyeaon Cho, Junichi Sadoshima, Shin Ichi Oka

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article numbere005529
JournalCirculation: Heart Failure
Volume12
Issue number3
DOIs
Publication statusPublished - 2019 Mar 1

Keywords

  • RNA polymerase II
  • chromatin
  • energy metabolism
  • heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Bhat, S., Chin, A., Shirakabe, A., Ikeda, Y., Ikeda, S., Zhai, P., Hsu, C. P., Sayed, D., Abdellatif, M., Byun, J., Schesing, K., Tang, F., Tian, Y., Babu, G., Ralda, G., Warren, J. S., Cho, J., Sadoshima, J., & Oka, S. I. (2019). 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. Circulation: Heart Failure, 12(3), [e005529]. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005529