Pgc-1α Senses the CBC of Pre-mRNA To Dictate the Fate of Promoter-Proximally Paused Rnapii

Authors

Xavier Rambout
Hana Cho
Roméo Blanc
Qing Lyu
Joseph M Miano
Joe V Chakkalakal
Geoffrey M Nelson
Hari K Yalamanchili
Karen Adelman
Lynne E Maquat

Language

English

Publication Date

1-19-2023

Journal

Molecular Cell

DOI

10.1016/j.molcel.2022.12.022

PMID

36669479

PMCID

PMC9951270

PubMedCentral® Posted Date

1-19-2024

PubMedCentral® Full Text Version

Author MSS

Abstract

PGC-1α is well established as a metazoan transcriptional coactivator of cellular adaptation in response to stress. However, the mechanisms by which PGC-1α activates gene transcription are incompletely understood. Here, we report that PGC-1α serves as a scaffold protein that physically and functionally connects the DNA-binding protein estrogen-related receptor α (ERRα), cap-binding protein 80 (CBP80), and Mediator to overcome promoter-proximal pausing of RNAPII and transcriptionally activate stress-response genes. We show that PGC-1α promotes pausing release in a two-arm mechanism (1) by recruiting the positive transcription elongation factor b (P-TEFb) and (2) by outcompeting the premature transcription termination complex Integrator. Using mice homozygous for five amino acid changes in the CBP80-binding motif (CBM) of PGC-1α that destroy CBM function, we show that efficient differentiation of primary myoblasts to myofibers and timely skeletal muscle regeneration after injury require PGC-1α binding to CBP80. Our findings reveal how PGC-1α activates stress-response gene transcription in a previously unanticipated pre-mRNA quality-control pathway.

Keywords

Animals, Mice, DNA-Binding Proteins, Muscle, Skeletal, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Promoter Regions, Genetic, RNA Cap-Binding Proteins, RNA Polymerase II, RNA Precursors, Transcription Factors, Transcription, Genetic, PGC-1α, ERRα, gene transcription, cap-binding complex, CBP80, Mediator, P-TEFb, promoter-proximal pausing, Integrator, pre-mRNP quality control, myogenesis, skeletal-muscle regeneration, interferon signaling

Published Open-Access

yes

Recommended Citation

Rambout, Xavier; Cho, Hana; Blanc, Roméo; et al., "Pgc-1α Senses the CBC of Pre-mRNA To Dictate the Fate of Promoter-Proximally Paused Rnapii" (2023). Children’s Nutrition Research Center Staff Publications. 314.
https://digitalcommons.library.tmc.edu/staff_pub/314