Characterization of a REST-Regulated Internal Promoter in the Schizophrenia Genome-Wide Associated Gene MIR137.
Characterization of a REST-Regulated Internal Promoter in the Schizophrenia Genome-Wide Associated Gene MIR137.
复制标题
精神分裂症基因组相关基因miR137中静止调节的内部启动子的表征。
DOI：
10.1093/schbul/sbu117
复制
发表时间：
2015-05
影响因子：
6.6
通讯作者：
Quinn JP
中科院分区：
文献类型：
--
作者：
Warburton A;Breen G;Rujescu D;Bubb VJ;Quinn JP
MIR 137通过与内含子单核苷酸多态性（SNP）rs 1625579的关联，已被鉴定为精神分裂症的候选基因。SNP的位置表明miR-137表达的转录或转录后调节可能是精神分裂症的基础。我们鉴定并验证了与miR-137本身相邻的MIR 137基因的新启动子，其可以指导编码miR-137的不同mRNA同种型的表达。内源性基因表达和报告基因分析确定，这种内部启动子受阻遏元件-1沉默转录因子（REST）的调控，该因子以前与精神分裂症相关的途径有关。REST的不同亚型介导该位点的差异表达，表明这些亚型的相对水平对miR-137表达谱很重要。内部启动子含有与前体miR-137序列相邻的可变数目串联重复（VNTR）结构域。由该启动子指导的报告基因活性通过VNTR的基因型进行修饰。在对可卡因的反应中也观察到差异表达，已知可卡因调节SH-SY 5 Y细胞中的REST途径。我们的数据支持这样的假设，即“基因×环境”相互作用可以通过这种内部启动子改变miR-137的表达水平，并且VNTR的基因型可以调节转录反应。我们证明，该启动子区域与rs 1625579不平衡，因此将提供一个独特的途径来潜在地改变miR-137水平以响应环境线索。
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.
登录
查看更多内容
影响因子：
9.8
作者：
ENCODE Project Consortium
通讯作者：
ENCODE Project Consortium
影响因子：
4.7
作者：
Ali FR;Vasiliou SA;Haddley K;Paredes UM;Roberts JC;Miyajima F;Klenova E;Bubb VJ;Quinn JP
通讯作者：
Quinn JP
影响因子：
4.8
作者：
Abramovitz, Lilach;Shapira, Tamar;Vardimon, Lily
通讯作者：
Vardimon, Lily
影响因子：
2.9
作者：
Howard, M. R.;Millward-Sadler, S. J.;Quinn, J. P.
通讯作者：
Quinn, J. P.
DOI：
10.1073/pnas.0401827101
发表时间：
2004-07-13
影响因子：
11.1
作者：
Bruce, AW;Donaldson, IJ;Buckley, NJ
通讯作者：
Buckley, NJ