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

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. Spiegelman

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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 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.

Keywords: GA repeat binding protein computational biology diabetes estrogen receptor related alpha microarray mitochondria mitochondrial biogenesis oxidative phosphorylation transcriptional network

Supplemental Data

Description	Link/Filename
PNAS Supplemental Information	http://www.pnas.org/cgi/content/full/0401401101/DC1
PGC-1-alpha timecourse (scaled expression data)	Scaled_Expression_Data.xls
Mouse promoters	refGene_mm3_PERI_TSS_1000
Mouse:human masked promoters	mm3_1k_1k_70_10_mouse
Gene list for Figure 1 correlogram	5034_Genes_Correlogram_Figure_1.xls