Proc. Natl. Acad. Sci. USA. Published: 2004.04.19
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. Shulman, Richard A. Heyman, Eric S. Lander, and Bruce M. SpiegelmanRead Manuscript
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 co-activator peroxisome proliferator-activated receptor-g co-activator-1a (PGC-1a). By combining PGC-1a-induced genomewide transcriptional profiles with a computational strategy to detect cis-regulatory motifs, we identified estrogen receptor-related receptor-a (Erra) and GA-binding protein a (Gabpa) as key transcription factors regulating the OXPHOS pathway. Interestingly, the genes encoding these two transcription factors are themselves PGC-1a-inducible and contain variants of both motifs near their promoters. Cellular assays confirmed that Erra and Gabpa partner with PGC-1a in muscle to form a double-positive feedback loop that drives the expression of many OXPHOS genes. By using a synthetic inhibitor of Erra, we demonstrated its key role in PGC-1a 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-1a action in the OXPHOS pathway, and suggest that Erra agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.
|PNAS Supplemental Information||http://www.pnas.org/cgi/content/full/0401401101/DC1|
|PGC-1-alpha timecourse (scaled expression data)||Scaled_Expression_Data.xls|
|Mouse:human masked promoters||mm3_1k_1k_70_10_mouse|
|Gene list for Figure 1 correlogram||5034_Genes_Correlogram_Figure_1.xls|