Errα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle
- 20 April 2004
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 101 (17), 6570-6575
- https://doi.org/10.1073/pnas.0401401101
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 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 alpha 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 Erralpha and GA-binding protein a partner with PGC-1alpha in muscle to form a double-positive-feedback loop that drives the expression of many OXPHOS genes. By using a synthetic inhibitor of Erralpha, 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 Erralpha agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.Keywords
This publication has 36 references indexed in Scilit:
- Reduced Fat Mass in Mice Lacking Orphan Nuclear Receptor Estrogen-Related Receptor αMolecular and Cellular Biology, 2003
- Bioenergetic Analysis of Peroxisome Proliferator-activated Receptor γ Coactivators 1α and 1β (PGC-1α and PGC-1β) in Muscle CellsPublished by Elsevier BV ,2003
- PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesNature Genetics, 2003
- Sequencing and comparison of yeast species to identify genes and regulatory elementsNature, 2003
- Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibresNature, 2002
- An algorithm for finding protein–DNA binding sites with applications to chromatin- immunoprecipitation microarray experimentsNature Biotechnology, 2002
- A Genomic Regulatory Network for DevelopmentScience, 2002
- The α and β Subunits of the GA-binding Protein Form a Stable Heterodimer in SolutionPublished by Elsevier BV ,2000
- Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1Cell, 1999
- The Structure of GABPα/β: An ETS Domain- Ankyrin Repeat Heterodimer Bound to DNAScience, 1998