Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA.
Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):E962-71. doi: 10.1073/pnas.1121568109. Epub 2012 Feb 27.
Dysregulation of the transcriptional repressor element-1 silencing transcription factor (REST)/neuron-restrictive silencer factor is important in a broad range of diseases, including cancer, diabetes, and heart disease. The role of REST-dependent epigenetic modifications in neurodegeneration is less clear. Here, we show that neuronal insults trigger activation of REST and CoREST in a clinically relevant model of ischemic stroke and that REST binds a subset of "transcriptionally responsive" genes (gria2, grin1, chrnb2, nefh, nfκb2, trpv1, chrm4, and syt6), of which the AMPA receptor subunit GluA2 is a top hit. Genes with enriched REST exhibited decreased mRNA and protein. We further show that REST assembles with CoREST, mSin3A, histone deacetylases 1 and 2, histone methyl-transferase G9a, and methyl CpG binding protein 2 at the promoters of target genes, where it orchestrates epigenetic remodeling and gene silencing. RNAi-mediated depletion of REST or administration of dominant-negative REST delivered directly into the hippocampus in vivo prevents epigenetic modifications, restores gene expression, and rescues hippocampal neurons. These findings document a causal role for REST-dependent epigenetic remodeling in the neurodegeneration associated with ischemic stroke and identify unique therapeutic targets for the amelioration of hippocampal injury and cognitive deficits.
转录抑制因子-1 沉默转录因子（REST）/神经元抑制因子的转录失调在多种疾病中都很重要，包括癌症、糖尿病和心脏病。REST 依赖性表观遗传修饰在神经退行性变中的作用尚不清楚。在这里，我们发现在缺血性中风的临床相关模型中，神经元损伤会触发 REST 和 CoREST 的激活，并且 REST 结合了一组“转录反应性”基因（gria2、grin1、chrnb2、nefh、nfκb2、trpv1、chrm4 和 syt6），其中 AMPA 受体亚基 GluA2 是最重要的。富含 REST 的基因表现出 mRNA 和蛋白质减少。我们进一步表明，REST 与 CoREST、mSin3A、组蛋白去乙酰化酶 1 和 2、组蛋白甲基转移酶 G9a 和甲基化 CpG 结合蛋白 2 在靶基因的启动子上组装，在那里它协调表观遗传重塑和基因沉默。体内直接在海马体中递送 RNAi 介导的 REST 耗竭或显性负性 REST 可防止表观遗传修饰，恢复基因表达并挽救海马神经元。这些发现证明了 REST 依赖性表观遗传重塑在与缺血性中风相关的神经退行性变中的因果作用，并确定了改善海马损伤和认知缺陷的独特治疗靶点。
