Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Neurochem Int. 2021 Sep;148:105074. doi: 10.1016/j.neuint.2021.105074. Epub 2021 May 24.
Huntington's disease (HD) is a devastating and fatal monogenic neurodegenerative disorder characterized by progressive loss of selective neurons in the brain and is caused by an abnormal expansion of CAG trinucleotide repeats in a coding exon of the huntingtin (HTT) gene. Progressive gene expression changes that begin at premanifest stages are a prominent feature of HD and are thought to contribute to disease progression. Increasing evidence suggests the critical involvement of epigenetic mechanisms in abnormal transcription in HD. Genome-wide alterations of a number of epigenetic modifications, including DNA methylation and multiple histone modifications, are associated with HD, suggesting that mutant HTT causes complex epigenetic abnormalities and chromatin structural changes, which may represent an underlying pathogenic mechanism. The causal relationship of specific epigenetic changes to early transcriptional alterations and to disease pathogenesis require further investigation. In this article, we review recent studies on epigenetic regulation in HD with a focus on DNA and histone modifications. We also discuss the contribution of epigenetic modifications to HD pathogenesis as well as potential mechanisms linking mutant HTT and epigenetic alterations. Finally, we discuss the therapeutic potential of epigenetic-based treatments.
亨廷顿病（HD）是一种破坏性和致命的单基因神经退行性疾病，其特征是大脑中选择性神经元进行性丧失，由亨廷顿（HTT）基因编码外显子中 CAG 三核苷酸重复异常扩展引起。在疾病前阶段开始的进行性基因表达变化是 HD 的一个突出特征，被认为有助于疾病进展。越来越多的证据表明，表观遗传机制在 HD 中的异常转录中具有关键作用。与 HD 相关的是许多表观遗传修饰（包括 DNA 甲基化和多种组蛋白修饰）的全基因组改变，这表明突变 HTT 导致复杂的表观遗传异常和染色质结构改变，这可能代表潜在的致病机制。特定表观遗传变化与早期转录改变和疾病发病机制的因果关系需要进一步研究。本文综述了 HD 中表观遗传调控的最新研究进展，重点关注 DNA 和组蛋白修饰。我们还讨论了表观遗传修饰对 HD 发病机制的贡献，以及突变 HTT 和表观遗传改变之间的潜在联系。最后，我们讨论了基于表观遗传的治疗的治疗潜力。
