Collins A L, Kim Y, Bloom R J, Kelada S N, Sethupathy P, Sullivan P F
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
1] Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Transl Psychiatry. 2014 Jul 1;4(7):e404. doi: 10.1038/tp.2014.42.
Genome-wide association studies (GWAS) have strongly implicated MIR137 (the gene encoding the microRNA miR-137) in schizophrenia. A parsimonious hypothesis is that a pathway regulated by miR-137 is important in the etiology of schizophrenia. Full evaluation of this hypothesis requires more definitive knowledge about biological targets of miR-137, which is currently lacking. Our goals were to expand knowledge of the biology of miR-137 by identifying its empirical targets, and to test whether the resulting lists of direct and indirect targets were enriched for genes and pathways involved in risk for schizophrenia. We overexpressed miR-137 in a human neural stem cell line and analyzed gene expression changes at 24 and 48 h using RNA sequencing. Following miR-137 overexpression, 202 and 428 genes were differentially expressed after 24 and 48 h. Genes differentially expressed at 24 h were enriched for transcription factors and cell cycle genes, and differential expression at 48 h affected a wider variety of pathways. Pathways implicated in schizophrenia were upregulated in the 48 h findings (major histocompatibility complex, synapses, FMRP interacting RNAs and calcium channels). Critically, differentially expressed genes at 48 h were enriched for smaller association P-values in the largest published schizophrenia GWAS. This work provides empirical support for a role of miR-137 in the etiology of schizophrenia.
全基因组关联研究（GWAS）已有力地表明MIR137（编码微小RNA miR - 137的基因）与精神分裂症有关。一个简洁的假说是，由miR - 137调控的一条通路在精神分裂症的病因学中很重要。对这一假说的全面评估需要对miR - 137的生物学靶点有更确切的了解，而目前尚缺乏这方面的知识。我们的目标是通过确定miR - 137的实际靶点来扩展对其生物学特性的认识，并测试由此得到的直接和间接靶点列表是否富含与精神分裂症风险相关的基因和通路。我们在一种人类神经干细胞系中过表达miR - 137，并使用RNA测序分析24小时和48小时时的基因表达变化。在miR - 137过表达后，24小时和48小时分别有202个和428个基因差异表达。在24小时差异表达的基因富含转录因子和细胞周期基因，48小时的差异表达影响了更广泛的多种通路。在48小时的研究结果中，与精神分裂症相关的通路被上调（主要组织相容性复合体、突触、FMRP相互作用RNA和钙通道）。至关重要的是，在已发表的最大规模精神分裂症GWAS中，48小时差异表达的基因在较小的关联P值上富集。这项工作为miR - 137在精神分裂症病因学中的作用提供了实证支持。
