Reprogramming to recover youthful epigenetic information and restore vision

Abstract

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 capacity1,2,3. 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 capacity5,6,7. 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.

衰老会导致组织功能障碍和死亡。衰老的一个可能原因是表观遗传噪声的积累破坏了基因表达模式，导致组织功能和再生能力下降。DNA甲基化模式会随着时间的推移发生改变，这构成了衰老的基础，但尚不清楚年龄较大的个体是否保留恢复这些模式所需的信息—如果是的话，这是否能改善组织功能还尚不清楚。随着时间的流逝，中枢神经系统（CNS）失去功能和再生能力。使用眼睛作为模型中枢神经系统组织，发现小鼠视网膜神经节细胞中Oct4（也称为Pou5f1），Sox2和Klf4基因（OSK）的异位表达可恢复年轻的DNA甲基化和转录组范式，促进损伤后轴突再生，并能逆转青光眼小鼠模型和老年小鼠的视力丧失。OSK诱导的轴突再生和视觉重编程的作用发挥需要DNA脱甲基酶TET1和TET2的存在。这些数据表明，哺乳动物组织保留了年轻的表观遗传信息（部分通过DNA甲基化编码），可以用来改善组织功能和促进体内再生。

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