Reprogramming to recover youthful epigenetic information and restore vision

Dec 3, 2020Nature

Reversing aging-related changes in gene activity to restore vision

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Regenerative Health on OpenScience ↗PubMed ↗DOI ↗

Abstract

Ectopic expression of Oct4, Sox2, and Klf4 genes in mouse retinal ganglion cells restores youthful DNA methylation patterns and improves vision.

Ageing is associated with the accumulation of epigenetic noise that disrupts gene expression and tissue function.
Changes in DNA methylation patterns are used to measure biological age, but older individuals may still retain information to restore these patterns.
Restoration of youthful DNA methylation and transcriptomes was observed after expressing certain genes in mouse retinal ganglion cells.
Axon regeneration and vision recovery were promoted in mouse models of glaucoma and aged mice following gene expression changes.
The effects of gene-induced reprogramming on regeneration require specific DNA demethylases, TET1 and TET2.
Mammalian tissues may retain a record of youthful epigenetic information that can be accessed to enhance regenerative capacity.

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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 capacity. Changes to DNA methylation patterns over time form the basis of ageing clocks, 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 capacity. 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. 1-3 4 5-7

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Reprogramming to recover youthful epigenetic information and restore vision

Abstract

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