title: Regulation of corepressor alternative mRNA splicing by hormonal and metabolic signaling.
abstract: Alternative mRNA splicing diversifies the products encoded by the NCoR and SMRT corepressor loci. There is a programmed alteration in NCoR mRNA splicing during adipocyte differentiation from an NCoRω isoform, which contains three nuclear receptor interaction domains, to an NCoRδ isoform that contains two nuclear receptor interaction domains. This alternative mRNA splicing of NCoR has profound effects on adiposity and on diabetes in mouse models. We report here that dexamethasone, a powerful regulator of metabolism and of adipocyte differentiation, confers this change in NCoR mRNA splicing in cultured adipocytes. We also demonstrate that changes in dietary components can consistently, if moderately, modulate the total transcript levels and the mRNA splicing of NCoR and SMRT in both cultured cells and intact mice. This ability of alternative corepressor mRNA splicing to respond to nutritional changes confirms its importance in regulating glucose and lipid metabolism, and its promise as a therapeutic candidate for metabolic disorders such as type 2 diabetes.
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California at Davis, USA. Electronic address: snyder@ucdavis.edu.
authors.forename: Chelsea A
authors.initials: CA
authors.lastname: Snyder
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California at Davis, USA. Electronic address: mlgoodson@ucdavis.edu.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Goodson
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California at Davis, USA. Electronic address: acshroeder@ucdavis.edu.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Schroeder
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California at Davis, USA. Electronic address: mlprivalsky@ucdavis.edu.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Privalsky
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D017398:Alternative Splicing / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D051379:Mice; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: C539128:Ncor1 protein, mouse; C539131:Ncor2 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D012333:RNA, Messenger; D003907:Dexamethasone; D005947:Glucose
keywords: Alternative mRNA splicing; Corepressors; Isoforms; NCoR; SMRT; Transcriptional regulation