DNA到RNA到蛋白质的遗传信息的正确传递对于细胞命运控制、发育和健康至关重要。DNA、RNA、组蛋白和非组蛋白蛋白的甲基化是一种可逆的后合成修饰，它在多种生理过程中微调基因表达和功能。由基因突变或环境刺激引起的异常甲基化促进了各种疾病的发生并加速衰老，因此需要开发治疗方法来纠正致病性甲基化失衡。在本综述中，我们总结了甲基化在中心学说中的作用系统，其中包括甲基化“写入”、擦除、阅读和独立于阅读的输出。然后，我们讨论了系统失调如何导致神经系统疾病、癌症和衰老。目前在某些癌症中，针对这些修饰因子的小分子化合物疗法显示出了一定的成功。甲基组全覆盖作用和缺乏特异性导致了不良的生物学效应和细胞毒性，从而限制了它们的治疗应用，特别是对于具有单基因致病因素或甲基化变化方向不同的疾病。具有位点特异性甲基化操纵能力的新兴工具在解决这一困境方面具有巨大的潜力。随着传递工具的完善，这些新工具将有望推动甲基化领域的基础研究和临床转化。© 2023年 四川大学华西医院。

The proper transfer of genetic information from DNA to RNA to protein is essential for cell-fate control, development, and health. Methylation of DNA, RNAs, histones, and non-histone proteins is a reversible post-synthesis modification that finetunes gene expression and function in diverse physiological processes. Aberrant methylation caused by genetic mutations or environmental stimuli promotes various diseases and accelerates aging, necessitating the development of therapies to correct the disease-driver methylation imbalance. In this Review, we summarize the operating system of methylation across the central dogma, which includes writers, erasers, readers, and reader-independent outputs. We then discuss how dysregulation of the system contributes to neurological disorders, cancer, and aging. Current small-molecule compounds that target the modifiers show modest success in certain cancers. The methylome-wide action and lack of specificity lead to undesirable biological effects and cytotoxicity, limiting their therapeutic application, especially for diseases with a monogenic cause or different directions of methylation changes. Emerging tools capable of site-specific methylation manipulation hold great promise to solve this dilemma. With the refinement of delivery vehicles, these new tools are well positioned to advance the basic research and clinical translation of the methylation field.© 2023. West China Hospital, Sichuan University.