PGC 1α senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII

Published: 3 January 2023| Version 1 | DOI: 10.17632/39mxxdfkdn.1
Contributors:
,
Hana Cho,

Description

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: by recruiting the positive transcription elongation factor b (P-TEFb), and 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.

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Institutions

University of Rochester Medical Center

Categories

Fluorescence Microscopy, Western Blot, Agarose Gel Electrophoresis

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