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.
Original language | English (US) |
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Pages (from-to) | 186-202.e11 |
Journal | Molecular Cell |
Volume | 83 |
Issue number | 2 |
DOIs | |
State | Published - Jan 19 2023 |
Externally published | Yes |
Keywords
- CBP80
- ERRα
- Integrator
- Mediator
- P-TEFb
- PGC-1α
- cap-binding complex
- gene transcription
- interferon signaling
- myogenesis
- pre-mRNP quality control
- promoter-proximal pausing
- skeletal muscle regeneration
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology