Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington's disease
Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington's disease
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DOI：
10.1523/jneurosci.4278-06.2007
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发表时间：
2007-06-27
影响因子：
5.3
通讯作者：
Cattaneo, Elena
中科院分区：
文献类型：
--
作者：
Zuccato, Chiara;Belyaev, Nikolai;Cattaneo, Elena
亨廷顿蛋白是一种蛋白质，在亨廷顿病(HD)中发生突变，亨廷顿病是一种显性遗传性神经退行性疾病。我们先前提出，除了突变蛋白获得的毒性活性外，HD的选择性分子功能障碍可能代表野生型蛋白活性丧失的后果。我们首次报道了野生型亨廷顿蛋白正向影响脑源性神经营养因子(BDNF)基因的转录，BDNF是纹状体神经元的一种皮质来源的生存因子，主要受疾病的影响。亨廷顿蛋白的突变降低了BDNF基因的转录。一种机制涉及位于BDNF启动子内的抑制元件1/神经元限制性沉默元件(Re1/NRSE)的激活。我们现在发现，在HD细胞、动物模型和死后脑中，Re1沉默转录因子/神经元限制性沉默因子(REST/NRSF)抑制子的结合增加发生在多个基因组Re1/NRSE位点，导致Re1/NRSE介导的基因转录减少。在内源性亨廷顿蛋白缺乏的细胞和脑组织中产生相同的分子表型，从而直接验证了HD的功能丧失假说。通过芯片(染色质免疫沉淀)芯片方法，我们检测了多个REST/NRSF靶基因在死后HD脑中的占有率，提供了该技术应用于神经退行性疾病的第一个例子。最后，我们发现，REST/NRSF结合的减弱可以恢复BDNF水平，这表明解除REST/NRSF介导的抑制可以恢复HD神经元基因的异常转录。
Huntingtin is a protein that is mutated in Huntington's disease (HD), a dominant inherited neurodegenerative disorder. We previously proposed that, in addition to the gained toxic activity of the mutant protein, selective molecular dysfunctions in HD may represent the consequences of the loss of wild- type protein activity. We first reported that wild-type huntingtin positively affects the transcription of the brain-derived neurotrophic factor (BDNF) gene, a cortically derived survival factor for the striatal neurons that are mainly affected in the disease. Mutation in huntingtin decreases BDNF gene transcription. One mechanism involves the activation of repressor element 1/neuron-restrictive silencer element (RE1/NRSE) located within the BDNF promoter. We now show that increased binding of the RE1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) repressor occurs at multiple genomic RE1/NRSE loci in HD cells, in animal models, and in postmortem brains, resulting in a decrease of RE1/NRSE-mediated gene transcription. The same molecular phenotype is produced in cells and brain tissue depleted of endogenous huntingtin, thereby directly validating the loss- of-function hypothesis of HD. Through a ChIP (chromatin immunoprecipitation)-on-chip approach, we examined occupancy of multiple REST/NRSF target genes in the postmortem HD brain, providing the first example of the application of this technology to neurodegenerative diseases. Finally, we show that attenuation of REST/NRSF binding restores BDNF levels, suggesting that relief of REST/NRSF mediated repression can restore aberrant neuronal gene transcription in HD.