PGC-1α senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII.
Mol Cell
; 83(2): 186-202.e11, 2023 Jan 19.
Article
em En
| MEDLINE
| ID: mdl-36669479
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.
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Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Precursores de RNA
Limite:
Animals
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article