title: Characterization of a REST-Regulated Internal Promoter in the Schizophrenia Genome-Wide Associated Gene MIR137.
abstract: MIR137 has been identified as a candidate gene for schizophrenia from genome-wide association studies via association with an intronic single nucleotide polymorphism (SNP), rs1625579. The location of the SNP suggests one mechanism in which transcriptional or posttranscriptional regulation of miR-137 expression could underlie schizophrenia. We identified and validated a novel promoter of the MIR137 gene adjacent to miR-137 itself which can direct the expression of distinct mRNA isoforms encoding miR-137. Analysis of both endogenous gene expression and reporter gene assays determined that this internal promoter is regulated by repressor element-1 silencing transcription factor (REST), which has previously been associated with pathways linked to schizophrenia. Distinct isoforms of REST mediate differential expression at this locus, suggesting the relative levels of these isoforms are important for miR-137 expression profiles. The internal promoter contains a variable number tandem repeat (VNTR) domain adjacent to the pre-miR-137 sequence. The reporter gene activity directed by this promoter was modified by the genotype of the VNTR. Differential expression was also observed in response to cocaine, which is known to regulate the REST pathway in SH-SY5Y cells. Our data support the hypothesis that a "gene × environment" interaction could modify the level of miR-137 expression via this internal promoter and that the genotype of the VNTR could modulate transcriptional responses. We demonstrate that this promoter region is not in disequilibrium with rs1625579 and therefore would supply a distinct pathway to potentially alter miR-137 levels in response to environmental cues.
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK;
authors.forename: Alix
authors.initials: A
authors.lastname: Warburton
authors.affiliation: King's College London, MRC Social Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK; National Institute for Health Research (NIHR), Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King's College London SE5 8DF, UK;
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.affiliation: Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK;
authors.forename: Vivien J
authors.initials: VJ
authors.lastname: Bubb
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK; jquinn@liverpool.ac.uk.
authors.forename: John P
authors.initials: JP
authors.lastname: Quinn
mesh_terms: D045744:Cell Line, Tumor; D015870:Gene Expression / Q000235:genetics*; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D018598:Minisatellite Repeats / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D035683:MicroRNAs; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C545567:MIRN137 microRNA, human
keywords: cocaine; gene environment interaction; microRNA-137; variable number tandem repeat