Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA.
Neuropsychopharmacology. 2013 Jan;38(1):167-82. doi: 10.1038/npp.2012.134. Epub 2012 Aug 15.
Epigenetic remodeling and modifications of chromatin structure by DNA methylation and histone modifications represent central mechanisms for the regulation of neuronal gene expression during brain development, higher-order processing, and memory formation. Emerging evidence implicates epigenetic modifications not only in normal brain function, but also in neuropsychiatric disorders. This review focuses on recent findings that disruption of chromatin modifications have a major role in the neurodegeneration associated with ischemic stroke and epilepsy. Although these disorders differ in their underlying causes and pathophysiology, they share a common feature, in that each disorder activates the gene silencing transcription factor REST (repressor element 1 silencing transcription factor), which orchestrates epigenetic remodeling of a subset of 'transcriptionally responsive targets' implicated in neuronal death. Although ischemic insults activate REST in selectively vulnerable neurons in the hippocampal CA1, seizures activate REST in CA3 neurons destined to die. Profiling the array of genes that are epigenetically dysregulated in response to neuronal insults is likely to advance our understanding of the mechanisms underlying the pathophysiology of these disorders and may lead to the identification of novel therapeutic strategies for the amelioration of these serious human conditions.
DNA 甲基化和组蛋白修饰引起的染色质结构的表观遗传重塑和修饰，代表了脑发育、高级处理和记忆形成过程中神经元基因表达调控的中心机制。新出现的证据表明，表观遗传修饰不仅与正常的大脑功能有关，而且与神经精神疾病有关。这篇综述重点介绍了最近的发现，即染色质修饰的破坏在与缺血性中风和癫痫相关的神经退行性变中起主要作用。尽管这些疾病在其根本原因和病理生理学上有所不同，但它们有一个共同的特征，即每种疾病都会激活基因沉默转录因子 REST（抑制元件 1 沉默转录因子），它协调一组“转录反应靶标”的表观遗传重塑，这些靶标与神经元死亡有关。尽管缺血性损伤会选择性地激活海马 CA1 中易受损伤的神经元中的 REST，但癫痫发作会激活 CA3 神经元中的 REST，这些神经元注定会死亡。对神经元损伤后表观遗传失调的基因进行分析，可能会增进我们对这些疾病病理生理学基础机制的理解，并可能为改善这些严重的人类疾病找到新的治疗策略。
