Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 17, Pages 6570-6575Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0401401101
Keywords
-
Categories
Ask authors/readers for more resources
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 gamma coactivator-1alpha (PGC-1alpha). By combining PGC-1alpha-induced genome-wide transcriptional profiles with a computational strategy to detect cis-regulatory motifs, we identified estrogen-related receptor alpha (Erralpha) and GA repeat-binding protein a as key transcription factors regulating the OXPHOS pathway. Interestingly, the genes encoding these two transcription factors are themselves PGC-1alpha-inducible and contain variants of both motifs near their promoters. Cellular assays confirmed that Erra and GA-binding protein a partner with PGC-1alpha a 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-1alpha-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-1alpha action in the OXPHOS pathway, and suggest that Erra agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available