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

doi:10.1161/CIRCHEARTFAILURE.118.005529

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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

Journal article

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Peer reviewed

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, …

Circulation. Heart failure, Vol.12(3), pp.e005529-e005529

03/2019

DOI: https://doi.org/10.1161/CIRCHEARTFAILURE.118.005529

PMCID: PMC6392084

PMID: 30798619

Abstract

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics

Animals

Down-Regulation

Heart Failure - genetics

RNA Polymerase II - genetics

Mice

RNA Polymerase II - metabolism

Promoter Regions, Genetic - genetics

Disease Models, Animal

Mice, Knockout

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. 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. 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.

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Title: 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
Creators: Santosh Bhat - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Adave Chin - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Akihiro Shirakabe - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Yoshiyuki Ikeda - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Shohei Ikeda - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Peiyong Zhai - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Chiao-Po Hsu - Division of Cardiovascular Surgery, Department of Surgery, Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-p.H.)
Danish Sayed - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Maha Abdellatif - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Jaemin Byun - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Kevin Schesing - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Fan Tang - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Yimin Tian - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Gopal Babu - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Guersom Ralda - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Junco S Warren - Nora Eccles Harrison Cardiovascular Research and Training Institute, Department of Internal Medicine, University of Utah, Salt Lake City (J.S.W.)
Jaeyeaon Cho - Department of Biomedical Science, College of Medicine, Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea (J.C.)
Junichi Sadoshima - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Shin-Ichi Oka - Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ (S.B., A.C., A.S., Y.I., S.I., P.Z., D.S., M.A., J.B., K.S., F.T., Y.T., G.B., G.R., J.S., S.-i.O.)
Publication Details: Circulation. Heart failure, Vol.12(3), pp.e005529-e005529
Date published: 03/2019
Grant note: R01 HL067724 / NHLBI NIH HHS R01 HL112330 / NHLBI NIH HHS R01 AG023039 / NIA NIH HHS R01 HL119726 / NHLBI NIH HHS R01 HL091469 / NHLBI NIH HHS R01 HL138720 / NHLBI NIH HHS
Academic Unit: Cell Biology and Molecular Medicine (NJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031654634204646