Huang Dishu, Zhao Wenjie, Sun Hong, Yang Chen, Jiang Li
Department of Neurology, National Clinical Research Center for Child Health and Disorders, International Science and Technology Cooperation base of Child development and Critical Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan Er Road, Yuzhong District, Chongqing, 400014, P. R. China.
General Medicine Ward, Chongqing Mental Health Center, Chongqing, 401147, P. R. China.
Mol Biol Rep. 2025 Jul 15;52(1):713. doi: 10.1007/s11033-025-10809-4.
5-mC DNA methylation is a fundamental epigenetic modification that plays a crucial role in neurodevelopment and neurological disorders. This review synthesizes the current understanding of 5-mC DNA methylation in neural system development and its implications in neurodevelopmental disorders. During normal neural development, 5-mC methylation precisely regulates neural stem cell differentiation and neuronal maturation through DNA methyltransferases (DNMTs) and methyl-CpG-binding domain (MBD) proteins. Disruption of these methylation patterns contributes to various neurodevelopmental disorders. In autism spectrum disorder (ASD), altered methylation patterns in specific genes like SHANK family and genome-wide methylation changes have been identified as potential diagnostic biomarkers. In fragile X syndrome, CGG trinucleotide repeat expansion increases methylation of the FMR1 gene promoter, leading to FMRP protein deficiency. Rett syndrome, primarily caused by MECP2 mutations, involves disrupted methylation-dependent transcriptional regulation. In epilepsy, DNA methylation abnormalities affect multiple epilepsy-related genes and may influence treatment responses to ketogenic diets. Despite these advances, the field faces significant challenges including tissue specificity issues, technical limitations in methylation detection, and therapeutic targeting difficulties. This review also discusses future perspectives, emphasizing the potential of DNA methylation as a therapeutic target and biomarker for neurodevelopmental disorders. Understanding these methylation mechanisms could lead to novel diagnostic tools and therapeutic strategies for various neurological conditions.
5-甲基胞嘧啶（5-mC）DNA甲基化是一种基本的表观遗传修饰，在神经发育和神经疾病中起着关键作用。本综述综合了目前对5-mC DNA甲基化在神经系统发育中的理解及其对神经发育障碍的影响。在正常神经发育过程中，5-mC甲基化通过DNA甲基转移酶（DNMTs）和甲基化CpG结合域（MBD）蛋白精确调节神经干细胞分化和神经元成熟。这些甲基化模式的破坏会导致各种神经发育障碍。在自闭症谱系障碍（ASD）中，已确定特定基因（如SHANK家族）的甲基化模式改变和全基因组甲基化变化是潜在的诊断生物标志物。在脆性X综合征中，CGG三核苷酸重复扩增增加了FMR1基因启动子的甲基化，导致FMRP蛋白缺乏。雷特综合征主要由MECP2突变引起，涉及甲基化依赖性转录调控的破坏。在癫痫中，DNA甲基化异常影响多个癫痫相关基因，并可能影响生酮饮食的治疗反应。尽管取得了这些进展，但该领域仍面临重大挑战，包括组织特异性问题、甲基化检测的技术限制以及治疗靶点的困难。本综述还讨论了未来的前景，强调了DNA甲基化作为神经发育障碍治疗靶点和生物标志物的潜力。了解这些甲基化机制可能会为各种神经疾病带来新的诊断工具和治疗策略。
