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PGC 1α Senses the CBC of Pre-mRNA to Dictate the Fate of Promoter-Proximally Paused RNAPII

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE197312 | GEO | 2023/01/19

REPOSITORIES: GEO

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

Project 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 (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.

| S-EPMC9951270 | biostudies-literature

PGC 1α Senses the CBC of Pre-mRNA to Dictate the Fate of Promoter-Proximally Paused RNAPII [PRO-seq]

Project description:Although PGC 1α is well-established as a transcriptional coactivator for the metabolic adaptation of mammalian cells to diverse physiological stresses, its molecular dynamics at the start and during gene transcription are incompletely understood. Previously, we defined a CBP80-binding motif (CBM) within PGC 1α that binds CBP80 at the 5′-cap of nascent transcripts deriving from PGC 1α-responsive genes. Binding verifies proper 5′-cap assembly, after which gene transcription is somehow promoted. Here, using protein immunoprecipitations, size-exclusion chromatography, PRO-seq, RNA-seq, native RIP-seq, RIP-seq footprinting and CUT&RUN, we report that PGC 1α, serving as a DNA−RNA conduit between promoter-bound ERRα and nascent transcript-bound CBP80, overcomes promoter-proximal pausing of RNAPII by competing against the premature transcription termination complex Integrator and also by recruiting P-TEFb. Using mice homozygous for five amino-acid changes in PGC 1α that destroy CBM function, we demonstrate that efficient differentiation of primary myoblasts to myofibers and effective regeneration of skeletal muscle after injury requires PGC 1α binding to CBP80.

2023-01-19 | GSE197275 | GEO

PGC 1α Senses the CBC of Pre-mRNA to Dictate the Fate of Promoter-Proximally Paused RNAPII [RNA-seq]

2023-01-19 | GSE197311 | GEO

PGC 1α Senses the CBC of Pre-mRNA to Dictate the Fate of Promoter-Proximally Paused RNAPII [RIP-seq footprint]

2023-01-19 | GSE197279 | GEO

PGC 1α Senses the CBC of Pre-mRNA to Dictate the Fate of Promoter-Proximally Paused RNAPII [RIP-seq native]

2023-01-19 | GSE197303 | GEO