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1476-468758878362020DecNatureNatureReprogramming to recover youthful epigenetic information and restore vision.124129124-12910.1038/s41586-020-2975-4Ageing 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.LuYuanchengY0000-0002-5982-3963Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.BrommerBenediktBDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.TianXiaoX0000-0001-5300-3596Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.KrishnanAnithaADepartment of Ophthalmology, Harvard Medical School, Boston, MA, USA.Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA.MeerMargaritaMDivision 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.WangChenCDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.VeraDaniel LDLDepartment of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.ZengQiuruiQDepartment of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.YuDoudouDDepartment of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.BonkowskiMichael SMSDepartment of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.YangJae-HyunJHDepartment of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.ZhouSonglinSDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.HoffmannEmma MEMDepartment of Ophthalmology, Harvard Medical School, Boston, MA, USA.Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA.KargMargarete MMMDepartment of Ophthalmology, Harvard Medical School, Boston, MA, USA.Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA.SchultzMichael BMBDepartment of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.KaneAlice EAEDepartment of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.DavidsohnNoahN0000-0002-4470-5665Department of Genetics, Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.KorobkinaEkaterinaEDepartment of Ophthalmology, Harvard Medical School, Boston, MA, USA.Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA.ChwalekKarolinaKDepartment of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.RajmanLuis ALADepartment of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.ChurchGeorge MGM0000-0003-3535-2076Department of Genetics, Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.HochedlingerKonradK0000-0001-5811-5386Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.GladyshevVadim NVN0000-0002-0372-7016Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.HorvathSteveS0000-0002-4110-3589Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.LevineMorgan EMEDepartment of Pathology, Yale School of Medicine, New Haven, CT, USA.Gregory-KsanderMeredith SMSDepartment of Ophthalmology, Harvard Medical School, Boston, MA, USA.Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA.KsanderBruce RBR0000-0001-5546-0360Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA.HeZhigangZ0000-0001-6080-6880Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.SinclairDavid ADA0000-0002-9936-436XDepartment of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA. david_sinclair@hms.harvard.edu.Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia. david_sinclair@hms.harvard.edu.engR01 EY021526EYNEI NIH HHSUnited StatesR01 AG065403AGNIA NIH HHSUnited StatesR24 EY028767EYNEI NIH HHSUnited StatesR37 GM065204GMNIGMS NIH HHSUnited StatesK99 AG068303AGNIA NIH HHSUnited StatesR21 EY030276EYNEI NIH HHSUnited StatesT32 AG023480AGNIA NIH HHSUnited StatesU54 HD090255HDNICHD NIH HHSUnited StatesR01 GM065204GMNIGMS NIH HHSUnited StatesR01 EY026939EYNEI NIH HHSUnited StatesP30 EY003790EYNEI NIH HHSUnited StatesR01 AG019719AGNIA NIH HHSUnited StatesR01 AG067782AGNIA NIH HHSUnited States5P30EY012196NHNIH HHSUnited StatesR01 EY025794EYNEI NIH HHSUnited StatesP30 EY012196EYNEI NIH HHSUnited StatesR37 AG028730AGNIA NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, Non-P.H.S.20201202
EnglandNature04104620028-08360DNA-Binding Proteins0KLF4 protein, human0Klf4 protein, mouse0Kruppel-Like Factor 40Kruppel-Like Transcription Factors0Octamer Transcription Factor-30Pou5f1 protein, mouse0Proto-Oncogene Proteins0SOXB1 Transcription Factors0Sox2 protein, mouse0TET1 protein, mouseEC 1.13.11.-DioxygenasesEC 1.13.11.-Tet2 protein, mouseIMNature. 2020 Dec;588(7836):34-36. doi: 10.1038/d41586-020-03119-1.33268872Nature. 2020 Dec;588(7837):209. doi: 10.1038/d41586-020-03403-0.33268879Nat Rev Genet. 2021 Feb;22(2):68-69. doi: 10.1038/s41576-020-00314-8.33318705Nat Rev Neurosci. 2021 Feb;22(2):73. doi: 10.1038/s41583-020-00422-8.33324008Cell Stem Cell. 2021 Jan 7;28(1):5-7. doi: 10.1016/j.stem.2020.12.006.33417872AginggeneticsphysiologyAnimalsAxonsphysiologyCell Line, TumorCell SurvivalCellular ReprogramminggeneticsDNA MethylationDNA-Binding ProteinsgeneticsDependovirusgeneticsDioxygenasesDisease Models, AnimalEpigenesis, GeneticEyecytologyinnervationpathologyFemaleGenetic VectorsgeneticsGlaucomageneticspathologyHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsgeneticsMiceMice, Inbred C57BLNerve RegenerationgeneticsOctamer Transcription Factor-3geneticsOptic Nerve InjuriesgeneticsProto-Oncogene ProteinsgeneticsRetinal Ganglion CellscytologySOXB1 Transcription FactorsgeneticsTranscriptomegeneticsVision, OculargeneticsphysiologyConflict of interest. D.A.S. is a consultant to, inventor of patents licensed to, board member of and equity owner of Iduna Therapeutics, a Life Biosciences company developing epigenetic reprograming therapies. D.A.S. is an advisor to Zymo Research, an epigenetics tools company. Additional disclosures are at https://genetics.med.harvard.edu/sinclair/people/sinclair-other.php. Y.L., L.A.R. and S.H. are equity owners of Iduna Therapeutics, a Life Biosciences company. D.L.V. is an advisor to Liberty Biosecurity. M.S.B. is a shareholder in MetroBiotech. K.C. is an equity owner in Life Biosciences and affiliates. N.D. and G.M.C. are co-founders of Rejuvenate Bio. Disclosures for G.M.C. can be found at http://arep.med.harvard.edu/gmc/tech.html. M.E.L. is a bioinformatics advisor to Elysium Health. Y.L., N.D. and D.A.S. are inventors on patents arising from this work (WO/2020/069373 and WO/2020/069339), filed by the President and Fellows of Harvard College. 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