Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes
Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes
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DOI：
10.1038/ng1219
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发表时间：
2003-09-01
期刊：
影响因子：
30.8
通讯作者：
Cattaneo, E
中科院分区：
文献类型：
--
作者：
Zuccato, C;Tartari, M;Cattaneo, E
亨廷顿蛋白在亨廷顿病中发生突变（1）。我们先前报道野生型而非突变型亨廷顿蛋白刺激编码脑源性神经营养因子（BDNF;参考文献2）的基因的转录。在这里，我们表明，神经元限制性沉默元件（NRSE）是野生型亨廷顿活性的BDNF启动子II的目标。野生型亨廷顿蛋白抑制NRSE的沉默活性，增加BDNF的转录。我们表明，这种效果发生通过细胞质隔离的阻遏元件-1转录因子/神经元限制性沉默因子（REST/NRSF），转录因子结合到NRSE 3，4。相反，在亨廷顿病中存在REST/NRSF在细胞核中的异常积累。我们发现野生型亨廷顿蛋白与REST/NRSF共免疫沉淀，并且在患有亨廷顿病的脑组织中发现较少的免疫沉淀物质。我们还报道了野生型亨廷顿蛋白作为其他参与维持神经元表型的含NRSE基因的正转录调节因子（5）。一致地，NRSE控制的神经元基因的表达丧失在患有亨廷顿病的细胞、小鼠和人脑中显示。我们的结论是野生型亨廷顿蛋白的行为在细胞质中的神经元，以调节其核NRSE结合位点的REST/NRSF的可用性，这种控制是失去了亨廷顿病的病理。这些数据确定了一种新的机制，通过这种机制，亨廷顿蛋白的突变导致神经元基因的转录丢失。
Huntingtin protein is mutated in Huntington disease(1). We previously reported that wild-type but not mutant huntingtin stimulates transcription of the gene encoding brain-derived neurotrophic factor (BDNF; ref. 2). Here we show that the neuron restrictive silencer element (NRSE) is the target of wildtype huntingtin activity on BDNF promoter II. Wild-type huntingtin inhibits the silencing activity of NRSE, increasing transcription of BDNF. We show that this effect occurs through cytoplasmic sequestering of repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF), the transcription factor that binds to NRSE3,4. In contrast, aberrant accumulation of REST/NRSF in the nucleus is present in Huntington disease. We show that wild-type huntingtin coimmunoprecipitates with REST/NRSF and that less immunoprecipitated material is found in brain tissue with Huntington disease. We also report that wild-type huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype(5). Consistently, loss of expression of NRSE-controlled neuronal genes is shown in cells, mice and human brain with Huntington disease. We conclude that wild-type huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. These data identify a new mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes.