Packer Amy N, Xing Yi, Harper Scott Q, Jones Lesley, Davidson Beverly L
Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
J Neurosci. 2008 Dec 31;28(53):14341-6. doi: 10.1523/JNEUROSCI.2390-08.2008.
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 bifunctional 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.
转录因子REST可使非神经元细胞中的神经元基因表达沉默。在神经元中，该蛋白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舞蹈病（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抑制序列并降低神经元基因表达。在这项研究中，我们发现相对于健康对照，HD患者皮质中几个具有上游RE1位点的微小RNA（miRNA）水平降低。有趣的是，其中之一，即双功能脑富集miR-9/miR-9*，靶向REST复合物的两个组分：miR-9靶向REST，miR-9*靶向CoREST。这些数据为REST沉默复合物与其所调控的miRNA之间的双负反馈环提供了证据。
