Errα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle

Vamsi K. Mootha, Christoph Handschin, Dan Arlow, Xiaohui Xie, Julie St. Pierre, Smita Sihag, Wenli Yang, David Altshuler, Pere Puigserver, Nick Patterson, Patricia J. Willy, Ira G. Schulman, Richard A. Heyman, Eric S. Lander, Bruce M. Spiegelman

    Research output: Contribution to journalArticlepeer-review

    526 Scopus citations


    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 γ coactivator-1α (PGC-1α). By combining PGC-1α-induced genome-wide transcriptional profiles with a computational strategy to detect cis-regulatory motifs, we identified estrogen-related receptor α (Errα) and GA repeat-binding protein α as key transcription factors regulating the OXPHOS pathway. Interestingly, the genes encoding these two transcription factors are themselves PGC-1α-inducible and contain variants of both motifs near their promoters. Cellular assays confirmed that Errα and GA-binding protein a partner with PGC-1α in muscle to form a double-positive-feedback loop that drives the expression of many OXPHOS genes. By using a synthetic inhibitor of Errα, we demonstrated its key role in PGC-1α-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-1α action in the OXPHOS pathway, and suggest that Errα agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.

    Original languageEnglish (US)
    Pages (from-to)6570-6575
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Issue number17
    StatePublished - Apr 27 2004

    ASJC Scopus subject areas

    • Genetics
    • General


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