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.

遗传信息从 DNA 到 RNA 再到蛋白质的正确转移对于细胞命运控制、发育和健康至关重要。DNA、RNA、组蛋白和非组蛋白的甲基化是一种可逆的合成后修饰，可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会促进各种疾病并加速衰老，因此需要开发疗法来纠正疾病驱动的甲基化失衡。在这篇综述中，我们总结了跨越中心法则的甲基化操作系统，其中包括写入器、擦除器、读取器和独立于读取器的输出。然后我们讨论该系统的失调如何导致神经系统疾病、癌症和衰老。目前针对修饰剂的小分子化合物在某些癌症中显示出一定的成功。甲基化范围内的作用和缺乏特异性导致不良的生物效应和细胞毒性，限制了它们的治疗应用，特别是对于具有单基因原因或不同方向甲基化变化的疾病。能够进行位点特异性甲基化操作的新兴工具有望解决这一困境。随着运载工具的完善，这些新工具完全有能力推进甲基化领域的基础研究和临床转化。