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Transcriptional coactivator PGC-1? contains a novel CBP80-binding motif that orchestrates efficient target gene expression.

ABSTRACT: Although peroxisome proliferator-activated receptor-? (PPAR?) coactivator 1? (PGC-1?) is a well-established transcriptional coactivator for the metabolic adaptation of mammalian cells to diverse physiological stresses, the molecular mechanism by which it functions is incompletely understood. Here we used in vitro binding assays, X-ray crystallography, and immunoprecipitations of mouse myoblast cell lysates to define a previously unknown cap-binding protein 80 (CBP80)-binding motif (CBM) in the C terminus of PGC-1?. We show that the CBM, which consists of a nine-amino-acid ? helix, is critical for the association of PGC-1? with CBP80 at the 5' cap of target transcripts. Results from RNA sequencing demonstrate that the PGC-1? CBM promotes RNA synthesis from promyogenic genes. Our findings reveal a new conduit between DNA-associated and RNA-associated proteins that functions in a cap-binding protein surveillance mechanism, without which efficient differentiation of myoblasts to myotubes fails to occur.

SUBMITTER: Cho H

PROVIDER: S-EPMC5959238 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Transcriptional coactivator PGC-1α contains a novel CBP80-binding motif that orchestrates efficient target gene expression.

Cho Hana H Rambout Xavier X Gleghorn Michael L ML Nguyen Phuong Quoc Thuc PQT Phipps Christopher R CR Miyoshi Keita K Myers Jason R JR Kataoka Naoyuki N Fasan Rudi R Maquat Lynne E LE

Genes & development 20180413 7-8

Although peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC-1α) is a well-established transcriptional coactivator for the metabolic adaptation of mammalian cells to diverse physiological stresses, the molecular mechanism by which it functions is incompletely understood. Here we used in vitro binding assays, X-ray crystallography, and immunoprecipitations of mouse myoblast cell lysates to define a previously unknown cap-binding protein 80 (CBP80)-binding motif (CBM) in the C ...[more]

PMID: 29654059

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Project description:The β3-adrenergic receptor (AR) signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The β3-AR signaling highly induces the expression of transcriptional coactivator PGC-1α and its splice variant N-terminal (NT)-PGC-1α, which in turn activate the transcription program of adaptive thermogenesis by co-activating a number of transcription factors. We previously reported that NT-PGC-1α is able to increase mitochondrial number and activity in cultured brown adipocytes by promoting the expression of mitochondrial and thermogenic genes. In the present study, we performed genome-wide profiling of NT-PGC-1α-responsive genes in brown adipocytes to identify genes potentially regulated by NT-PGC-1α. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1α are highly enriched in mitochondrial pathways including fatty acid transport and β-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1α in the enhancement of mitochondrial function. Moreover, canonical pathway analysis of NT-PGC-1α-responsive genes identified several metabolic pathways including glycolysis and fatty acid synthesis. In order to validate the identified genes in vivo, we utilized the FL-PGC-1α-/- mouse that is deficient in full-length PGC-1α (FL-PGC-1α) but expresses a slightly shorter and functionally equivalent form of NT-PGC-1α (NT-PGC-1α254). The β3-AR-induced increase of NT-PGC-1α254 in FL-PGC-1α-/- brown and white adipose tissue was closely associated with elevated expression of genes involved in thermogenesis, mitochondrial oxidative metabolism, glycolysis and fatty acid synthesis. Increased adipose tissue thermogenesis by β3-AR activation resulted in attenuation of adipose tissue expansion in FL-PGC-1α-/- adipose tissue under the high-fat diet condition. Together, the data strengthen our previous findings that NT-PGC-1α regulates mitochondrial genes involved in thermogenesis and oxidative metabolism in brown and white adipocytes and further suggest that NT-PGC-1α regulates a broad spectrum of genes to meet cellular needs for adaptive thermogenesis.

Dataset Information

Transcriptional coactivator PGC-1? contains a novel CBP80-binding motif that orchestrates efficient target gene expression.

Publications

Transcriptional coactivator PGC-1α contains a novel CBP80-binding motif that orchestrates efficient target gene expression.

Similar Datasets

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