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

doi:10.1073/pnas.0401401101

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

^*The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139; ^†Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and ^¶Dana–Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115; and ^**X-Ceptor Therapeutics Inc., San Diego, CA 92121

Contributed by Bruce M. Spiegelman, February 27, 2004

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 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.

Footnotes

↵ § To whom correspondence should be addressed at: (V.K.M.) Massachusetts Institute of Technology/Broad Institute, One Kendall Square, Building 300, Cambridge, MA 02139-1561. E-mail: vmootha{at}broad.mit.edu; or (B.M.S.) Dana–Farber Cancer Institute, Department of Cancer Biology, Smith Building SM958, One Jimmy Fund Way, Boston, MA 02115. E-mail: bruce_spiegelman{at}dfci.harvard.edu.
↵ ‡ V.K.M. and C.H. contributed equally to this work.
↵ ∥ Present address: Department of Cell Biology, Johns Hopkins University Medical School, Baltimore, MD 21205.
Abbreviations: OXPHOS, oxidative phosphorylation; PGC-1, peroxisome proliferator-activated receptor γ coactivator-1; Errα, estrogen-related receptor α; Gabp, GA repeat-binding protein; motifADE, motifs associated with differential expression; TSS, transcriptional start site; NRF, nuclear respiratory factor; MCAD, medium-chain acyl-CoA dehydrogenase; XCT790, 3-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-cyano-N-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-acrylamide.