title: Genomic convergence among ERRα, PROX1, and BMAL1 in the control of metabolic clock outputs.
abstract: 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 α (ERRα, 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 ERRα directly regulates all major components of the molecular clock. ERRα-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 ERRα-null mice exhibit time-dependent hypoglycemia and hypoinsulinemia, suggesting a role for ERRα in modulating insulin sensitivity and glucose handling during the 24-hour light/dark cycle. We also provide evidence that the newly identified ERRα 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 ERRα, PROX1, and BMAL1, an integral component of the molecular clock. These studies revealed the existence of transcriptional regulatory loops among ERRα, 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 ERRα, PROX1, and BMAL1 transcriptional activity thus identified a novel node in the molecular circuitry controlling the daily timing of metabolic processes.
authors: Goodman Cancer Research Centre, Montréal, Canada.
authors: Catherine R
authors: CR
authors: Dufour
authors: Marie-Pier
authors: MP
authors: Levasseur
authors: Nguyen Hoai Huong
authors: NH
authors: Pham
authors: Lillian J
authors: LJ
authors: Eichner
authors: Brian J
authors: BJ
authors: Wilson
authors: Alexis
authors: A
authors: Charest-Marcotte
authors: David
authors: D
authors: Duguay
authors: Jean-François
authors: JF
authors: Poirier-Héon
authors: Nicolas
authors: N
authors: Cermakian
authors: Vincent
authors: V
authors: Giguère
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D056926:CLOCK Proteins / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000097:blood; D002940:Circadian Rhythm; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005943:Gluconeogenesis; D006019:Glycolysis; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D017440:Photoperiod; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D056930:ARNTL Transcription Factors; D001647:Bile Acids and Salts; D001786:Blood Glucose; D056926:CLOCK Proteins; D002784:Cholesterol; D018398:Homeodomain Proteins; D007328:Insulin; D011960:Receptors, Estrogen; D014280:Triglycerides; D025521:Tumor Suppressor Proteins; D000097983:ERRalpha Estrogen-Related Receptor; D000098551:Prospero-Related Homeobox 1 Protein; C538961:Bmal1 protein, mouse; C538944:Clock protein, mouse