Reprogramming to recover youthful epigenetic information and restore vision
Authors: Xiao Tian
Michael B Schultz
Emma M Hoffmann
David A Sinclair
Songlin Zhou
Benedikt Brommer
Steve Horvath
Konrad Hochedlinger
Daniel L Vera
Morgan E Levine
Alice E Kane
Luis A Rajman
Yuancheng Lu
Karolina Chwalek
Margarita Meer
Margarete M Karg
Chen Wang
Jae-Hyun Yang
Ekaterina Korobkina
Michael S Bonkowski
Anitha Krishnan
Bruce R Ksander
Zhigang He
Noah Davidsohn
Vadim N Gladyshev
George M Church
Qiurui Zeng
Doudou Yu
Meredith S Gregory-Ksander
Journal: Nature (2020)
Discipline: Multidisciplinary
Keywords: Ageing; Epigenetic noise; DNA methylation patterns; Tissue function; Regenerative capacity
Affiliations: Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA., Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Department of Ophthalmology, Harvard Medical School, Boston, MA, USA., Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA., Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Department of Pathology, Yale School of Medicine, New Haven, CT, USA., Department of Genetics, Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA., Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA., Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA. ., Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia. .

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. 

Retracted: No

PubPeer comments:
 It is very surprising to see almost no IOP variations between 29 beads injected mice (figure 3b), though in extended data figure 9 it did show this bead model has variations in axon density and RGC density. Actually IOP measured by tonometer should have relatively bigger variations even in controls, even measured at the same time of day. , 
 There is controversy over where the notion that iPS  reprogramming factors can be used to induce rejuvenation without de-differentiation was first put forward and tested (see comments in https: pubpeer.com publications E006ECA3F03CA48839B631F5682C7A. It is this hypothesis that is tested in this work and other recent papers. ,