Reprogramming to recover youthful epigenetic information and restore vision

Yuancheng Lu, Benedikt Brommer, Xiao Tian, Anitha Krishnan, Margarita Meer, Chen Wang, Daniel L. Vera, Qiurui Zeng, Doudou Yu, Michael S. Bonkowski, Jae-Hyun Yang, Songlin Zhou, Emma M. Hoffmann, Margarete M. Karg, Michael B. Schultz, Alice E. Kane, Noah Davidsohn, Ekaterina Korobkina, Karolina Chwalek, Luis A. Rajman, George M. Church, Konrad Hochedlinger, Vadim N. Gladyshev, Steve Horvath, Morgan E. Levine, Meredith S. Gregory-Ksander, Bruce R. Ksander, Zhigang He and David A. Sinclair ()
Additional contact information
Yuancheng Lu: Harvard Medical School
Benedikt Brommer: Harvard Medical School
Xiao Tian: Harvard Medical School
Anitha Krishnan: Harvard Medical School
Margarita Meer: Harvard Medical School
Chen Wang: Harvard Medical School
Daniel L. Vera: Harvard Medical School
Qiurui Zeng: Harvard Medical School
Doudou Yu: Harvard Medical School
Michael S. Bonkowski: Harvard Medical School
Jae-Hyun Yang: Harvard Medical School
Songlin Zhou: Harvard Medical School
Emma M. Hoffmann: Harvard Medical School
Margarete M. Karg: Harvard Medical School
Michael B. Schultz: Harvard Medical School
Alice E. Kane: Harvard Medical School
Noah Davidsohn: Harvard University
Ekaterina Korobkina: Harvard Medical School
Karolina Chwalek: Harvard Medical School
Luis A. Rajman: Harvard Medical School
George M. Church: Harvard University
Konrad Hochedlinger: Massachusetts General Hospital
Vadim N. Gladyshev: Harvard Medical School
Steve Horvath: University of California Los Angeles
Morgan E. Levine: Yale School of Medicine
Meredith S. Gregory-Ksander: Harvard Medical School
Bruce R. Ksander: Harvard Medical School
Zhigang He: Harvard Medical School
David A. Sinclair: Harvard Medical School

Nature, 2020, vol. 588, issue 7836, 124-129

Abstract: 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 capacity1–3. 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.

Date: 2020
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DOI: 10.1038/s41586-020-2975-4

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