Identification and Potential Regulatory Properties of Evolutionary Conserved Regions (ECRs) at the Schizophrenia-Associated MIR137 Locus

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• 作者：Olympia Gianfrancesco ; Daniel Griffiths ; Paul Myers…
• 关键词：Schizophrenia ; microRNA ; 137 ; Gene regulation ; Gene expression ; Transcription ; Genetics
• 刊名：Journal of Molecular Neuroscience
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：60
• 期：2
• 页码：239-247
• 全文大小：2,142 KB
• 刊物主题：Neurosciences; Neurochemistry; Cell Biology; Proteomics; Neurology;
• 出版者：Springer US
• ISSN：1559-1166
• 卷排序：60

文摘

Genome-wide association studies (GWAS) have identified a region at chromosome 1p21.3, containing the microRNA MIR137, to be among the most significant associations for schizophrenia. However, the mechanism by which genetic variation at this locus increases risk of schizophrenia is unknown. Identifying key regulatory regions around MIR137 is crucial to understanding the potential role of this gene in the aetiology of psychiatric disorders. Through alignment of vertebrate genomes, we identified seven non-coding regions at the MIR137 locus with conservation comparable to exons (>70 %). Bioinformatic analysis using the Psychiatric Genomics Consortium GWAS dataset for schizophrenia showed five of the ECRs to have genome-wide significant SNPs in or adjacent to their sequence. Analysis of available datasets on chromatin marks and histone modification data showed that three of the ECRs were predicted to be functional in the human brain, and three in development. In vitro analysis of ECR activity using reporter gene assays showed that all seven of the selected ECRs displayed transcriptional regulatory activity in the SH-SY5Y neuroblastoma cell line. This data suggests a regulatory role in the developing and adult brain for these highly conserved regions at the MIR137 schizophrenia-associated locus and further that these domains could act individually or synergistically to regulate levels of MIR137 expression.