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. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. 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. Over time, the central nervous system (CNS) loses function and regenerative capacity 5– 7. Changes to DNA methylation patterns over time form the basis of ageing clocks 4, but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity 1– 3. jointly supervised this work.Īgeing is a degenerative process that leads to tissue dysfunction and death. helped with grant applications and project management. helped with plasmid constructs and AAV9 production. M.S.B., X.T., M.B.S., A.E.K., L.A.R., helped with systemic AAV9 experiments.

helped with transgenic mouse fibroblasts work.

conducted human methylation clock analysis. performed the RNA-seq and gene association analysis.

conducted ribosomal DNAm age analysis for mouse RGCs. contributed to the glaucoma and ageing studies. contributed to the optic nerve crush studies and imaging. was involved in all experiments and analyses. wrote the manuscript with input from all co-authors.

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