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PMID: 15100410 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 17 ·2004-04-27 ·Pages 6570-5

Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, Spiegelman BM

Abstract

Recent studies have shown that genes involved in oxidative phosphorylation (OXPHOS) exhibit reduced expression in skeletal muscle of diabetic and prediabetic humans. Moreover, these changes may be mediated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). By combining PGC-1alpha-induced genome-wide transcriptional profiles with a computational strategy to detect cis-regulatory motifs, we identified estrogen-related receptor alpha (Erralpha) and GA repeat-binding protein alpha as key transcription factors regulating the OXPHOS pathway. Interestingly, the genes encoding these two transcription factors are themselves PGC-1alpha-inducible and contain variants of both motifs near their promoters. Cellular assays confirmed that Erralpha and GA-binding protein a partner with PGC-1alpha in muscle to form a double-positive-feedback loop that drives the expression of many OXPHOS genes. By using a synthetic inhibitor of Erralpha, we demonstrated its key role in PGC-1alpha-mediated effects on gene regulation and cellular respiration. These results illustrate the dissection of gene regulatory networks in a complex mammalian system, elucidate the mechanism of PGC-1alpha action in the OXPHOS pathway, and suggest that Erralpha agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.

MeSH Terms
Animals Base Sequence DNA Primers DNA-Binding Proteins/genetics,physiology Diabetes Mellitus, Experimental/genetics,metabolism Evolution, Molecular GA-Binding Protein Transcription Factor Gene Expression Regulation Mice Oxidative Phosphorylation Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Polymerase Chain Reaction Receptors, Cytoplasmic and Nuclear/genetics,physiology Receptors, Estrogen/genetics,physiology Trans-Activators/physiology Transcription Factors/genetics,physiology Transcription, Genetic Transfection
Chemicals
DNA Primers DNA-Binding Proteins ERRalpha estrogen-related receptor GA-Binding Protein Transcription Factor Gabpa protein, mouse Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Ppargc1a protein, mouse Receptors, Cytoplasmic and Nuclear Receptors, Estrogen Trans-Activators Transcription Factors
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Mootha Vamsi K
The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139-1561, USA. vmootha@broad.mit.edu
Handschin Christoph
Arlow Dan
Xie Xiaohui
St Pierre Julie
Sihag Smita
Yang Wenli
Altshuler David
Puigserver Pere
Patterson Nick
Willy Patricia J
Schulman Ira G
Heyman Richard A
Lander Eric S
Spiegelman Bruce M
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0401401101
Email
vmootha@broad.mit.edu
Published
2004-04-27
Epub
2004-00-20
Pages
6570-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC404086
Subset
IM
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1073/pnas.0401401101 PMC Full Text View journal details
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