Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity1-3. Changes to DNA methylation patterns over time form the basis of ageing clocks4, but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity5-7. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information-encoded in part by DNA methylation-that can be accessed to improve tissue function and promote regeneration in vivo.

中文翻译：

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重新编程以恢复年轻的表观遗传信息并恢复视力

衰老是导致组织功能障碍和死亡的退化过程。提出的衰老原因是表观遗传噪声的积累会破坏基因表达模式，从而导致组织功能和再生能力下降 1-3。DNA 甲基化模式随时间的变化构成了衰老时钟的基础 4，但老年人是否保留了恢复这些模式所需的信息——如果是这样，这是否可以改善组织功能——尚不清楚。随着时间的推移，中枢神经系统 (CNS) 会失去功能和再生能力 5-7。使用眼睛作为模型 CNS 组织，在这里我们显示 Oct4（也称为 Pou5f1）、Sox2 和 Klf4 基因 (OSK) 在小鼠视网膜神经节细胞中的异位表达可恢复年轻的 DNA 甲基化模式和转录组，促进损伤后轴突再生，并逆转青光眼小鼠模型和老年小鼠的视力丧失。OSK 诱导的重编程对轴突再生和视觉的有益影响需要 DNA 去甲基化酶 TET1 和 TET2。这些数据表明哺乳动物组织保留了年轻表观遗传信息的记录——部分由 DNA 甲基化编码——可以访问这些信息以改善组织功能并促进体内再生。