Reprogramming to recover youthful epigenetic information and restore vision

Autor: Bruce R. Ksander, Morgan E. Levine, Emma Hoffmann, Luis A. Rajman, Zhigang He, Meredith S Gregory-Ksander, Michael Bonkowski, Anitha Krishnan, Jae-Hyun Yang, Chen Wang, Alice E. Kane, Ekaterina Korobkina, Songlin Zhou, Xiao Tian, Margarita Meer, George M. Church, Yu D, Michael B. Schultz, Karolina Chwalek, Noah Davidsohn, Steve Horvath, Yuancheng Lu, Qiurui Zeng, Konrad Hochedlinger, David A. Sinclair, Daniel L. Vera, Vadim N. Gladyshev, Margarete M. Karg, Benedikt Brommer
Rok vydání: 2020
Předmět:
Retinal Ganglion Cells
0301 basic medicine
Aging
Cell Survival
Genetic Vectors
Kruppel-Like Transcription Factors
Biology
Eye
Retinal ganglion
Article
Dioxygenases
Epigenesis
Genetic
Kruppel-Like Factor 4
Mice
03 medical and health sciences
0302 clinical medicine
SOX2
Cell Line
Tumor
Proto-Oncogene Proteins
medicine
Animals
Humans
Epigenetics
Axon
Vision
Ocular
Multidisciplinary
SOXB1 Transcription Factors
Regeneration (biology)
Glaucoma
DNA Methylation
Dependovirus
Cellular Reprogramming
Axons
Nerve Regeneration
Cell biology
DNA-Binding Proteins
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Optic Nerve Injuries
DNA methylation
Female
Ectopic expression
Transcriptome
Octamer Transcription Factor-3
Reprogramming
030217 neurology & neurosurgery
Zdroj: Nature
ISSN: 1476-4687
0028-0836
DOI: 10.1038/s41586-020-2975-4
Popis: 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. Expression of three Yamanaka transcription factors in mouse retinal ganglion cells restores youthful DNA methylation patterns, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice, suggesting that mammalian tissues retain a record of youthful epigenetic information that can be accessed to improve tissue function.
Databáze: OpenAIRE
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