The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington's disease.
The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington's disease.
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DOI：
10.1523/jneurosci.2390-08.2008
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发表时间：
2008-12-31
期刊：
影响因子：
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通讯作者：
Davidson BL
中科院分区：
文献类型：
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作者：
Packer AN;Xing Y;Harper SQ;Jones L;Davidson BL
转录因子 REST 沉默非神经元细胞中的神经元基因表达。在神经元中，该蛋白质部分通过与亨廷顿蛋白结合而被隔离在细胞质中。亨廷顿蛋白中的聚谷氨酰胺扩增会导致亨廷顿病 (HD)，并消除 REST 与亨廷顿蛋白的结合。因此，REST 易位至细胞核，占据 RE1 阻遏物序列并降低神经元基因表达。在这项工作中，我们发现与健康对照相比，HD 患者皮质中几种具有上游 RE1 位点的 microRNA (miRNA) 水平降低。有趣的是，其中之一，富含 miR-9/miR-9* 的双功能大脑，靶向 REST 复合物的两个组成部分：miR-9 靶向 REST，miR-9* 靶向 CoREST。这些数据为 REST 沉默复合物与其调节的 miRNA 之间的双重负反馈循环提供了证据。
The transcription factor REST silences neuronal gene expression in non-neuronal cells. In neurons, the protein is sequestered in the cytoplasm in part through binding to huntingtin. Polyglutamine expansions in huntingtin, which causes Huntington’s disease (HD), abrogates REST-huntingtin binding. Consequently, REST translocates to the nucleus, occupies RE1 repressor sequences and decreases neuronal gene expression. In this work, we found that levels of several microRNAs (miRNAs) with upstream RE1 sites are decreased in HD patient cortices relative to healthy controls. Interestingly, one of these, the bi-functional brain enriched miR-9/miR-9*, targets two components of the REST complex: miR-9 targets REST and miR-9* targets CoREST. These data provide evidence for a double negative feedback loop between the REST silencing complex and the miRNAs it regulates.