| First Author | Dufour CR | Year | 2011 |
| Journal | PLoS Genet | Volume | 7 |
| Issue | 6 | Pages | e1002143 |
| PubMed ID | 21731503 | Mgi Jnum | J:243803 |
| Mgi Id | MGI:5912582 | Doi | 10.1371/journal.pgen.1002143 |
| Citation | Dufour CR, et al. (2011) Genomic convergence among ERRalpha, PROX1, and BMAL1 in the control of metabolic clock outputs. PLoS Genet 7(6):e1002143 |
| abstractText | Metabolic homeostasis and circadian rhythms are closely intertwined biological processes. Nuclear receptors, as sensors of hormonal and nutrient status, are actively implicated in maintaining this physiological relationship. Although the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha, NR3B1) plays a central role in the control of energy metabolism and its expression is known to be cyclic in the liver, its role in temporal control of metabolic networks is unknown. Here we report that ERRalpha directly regulates all major components of the molecular clock. ERRalpha-null mice also display deregulated locomotor activity rhythms and circadian period lengths under free-running conditions, as well as altered circulating diurnal bile acid and lipid profiles. In addition, the ERRalpha-null mice exhibit time-dependent hypoglycemia and hypoinsulinemia, suggesting a role for ERRalpha in modulating insulin sensitivity and glucose handling during the 24-hour light/dark cycle. We also provide evidence that the newly identified ERRalpha corepressor PROX1 is implicated in rhythmic control of metabolic outputs. To help uncover the molecular basis of these phenotypes, we performed genome-wide location analyses of binding events by ERRalpha, PROX1, and BMAL1, an integral component of the molecular clock. These studies revealed the existence of transcriptional regulatory loops among ERRalpha, PROX1, and BMAL1, as well as extensive overlaps in their target genes, implicating these three factors in the control of clock and metabolic gene networks in the liver. Genomic convergence of ERRalpha, PROX1, and BMAL1 transcriptional activity thus identified a novel node in the molecular circuitry controlling the daily timing of metabolic processes. |
