TY - JOUR
T1 - Errα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle
AU - Mootha, Vamsi K.
AU - Handschin, Christoph
AU - Arlow, Dan
AU - Xie, Xiaohui
AU - St. Pierre, Julie
AU - Sihag, Smita
AU - Yang, Wenli
AU - Altshuler, David
AU - Puigserver, Pere
AU - Patterson, Nick
AU - Willy, Patricia J.
AU - Schulman, Ira G.
AU - Heyman, Richard A.
AU - Lander, Eric S.
AU - Spiegelman, Bruce M.
PY - 2004/4/27
Y1 - 2004/4/27
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.0401401101
DO - 10.1073/pnas.0401401101
M3 - Article
C2 - 15100410
AN - SCOPUS:2342477730
SN - 0027-8424
VL - 101
SP - 6570
EP - 6575
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 17
ER -