重复疾病,比如脆性X综合征,强直性肌营养不良,Friedreich共济失调,亨廷顿病,脊髓小脑共济失调,和一些形式的肌萎缩侧索硬化症,是由受影响个体中扩增的重复DNA序列引起的。个体开始出现症状的年龄,以及疾病的严重程度,部分由重复的大小决定。然而,重复区域及其周围区域的表观遗传状态在决定疾病发病年龄和疾病进展速度方面也起着重要作用。许多重复疾病在重复区域附近的CpG岛具有增加的甲基化的共同表观遗传模式。CpG岛是富含CG的序列,受甲基化严格调节,通常在基因组中的基因增强子或绝缘子元件中发现。CpG岛的甲基化可以抑制转录调节因子CTCF的结合,导致染色质封闭状态和基因下调。这些基因的下调导致一些疾病特异性症状。此外,甲基化对重复不稳定性的影响表明遗传和表观遗传相互作用,大量重复扩展的标志,导致连续几代疾病严重程度增加。在这次审查中,我们将讨论重复疾病的共同表观遗传模式,遗传学和表观遗传学是如何相互作用的,以及这如何与疾病表现有关。我们还讨论了目前可用的干细胞和小鼠模型,通常不概括人类疾病中观察到的表观遗传模式,并提出替代策略来研究表观遗传学在重复疾病中的作用。
Repeat diseases, such as fragile X syndrome, myotonic dystrophy, Friedreich ataxia, Huntington disease, spinocerebellar ataxias, and some forms of amyotrophic lateral sclerosis, are caused by repetitive DNA sequences that are expanded in affected individuals. The age at which an individual begins to experience symptoms, and the severity of disease, are partially determined by the size of the repeat. However, the epigenetic state of the area in and around the repeat also plays an important role in determining the age of disease onset and the rate of disease progression. Many repeat diseases share a common epigenetic pattern of increased methylation at CpG islands near the repeat region. CpG islands are CG-rich sequences that are tightly regulated by methylation and are often found at gene enhancer or insulator elements in the genome. Methylation of CpG islands can inhibit binding of the transcriptional regulator CTCF, resulting in a closed chromatin state and gene down regulation. The downregulation of these genes leads to some disease-specific symptoms. Additionally, a genetic and epigenetic interplay is suggested by an effect of methylation on repeat instability, a hallmark of large repeat expansions that leads to increasing disease severity in successive generations. In this review, we will discuss the common epigenetic patterns shared across repeat diseases, how the genetics and epigenetics interact, and how this could be involved in disease manifestation. We also discuss the currently available stem cell and mouse models, which frequently do not recapitulate epigenetic patterns observed in human disease, and propose alternative strategies to study the role of epigenetics in repeat diseases.