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Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming

Yuancheng Lu, Anitha Krishnan, Benedikt Brommer, Xiao Tian, Margarita Meer, Daniel L. Vera, Chen Wang, Qiurui Zeng, Doudou Yu, Michael S. Bonkowski, Jae-Hyun Yang, Emma M. Hoffmann, Songlin Zhou, Ekaterina Korobkina, Noah Davidsohn, Michael B. Schultz, Karolina Chwalek, Luis A. Rajman, George M. Church, Konrad Hochedlinger, Vadim N. Gladyshev, Steve Horvath, Meredith S. Gregory-Ksander, Bruce R. Ksander, Zhigang He, David A. Sinclair
doi: https://doi.org/10.1101/710210
Yuancheng Lu
1Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School
2Blavatnik Institute, Department of Genetics, Harvard Medical School
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Anitha Krishnan
3Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School
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Benedikt Brommer
4Boston Children’s Hospital, Department of Neurology, Harvard Medical School
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Xiao Tian
1Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School
2Blavatnik Institute, Department of Genetics, Harvard Medical School
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Margarita Meer
5Division of Genetics, Dept. of Medicine, Brigham and Women’s Hospital, Harvard Medical School
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Daniel L. Vera
1Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School
2Blavatnik Institute, Department of Genetics, Harvard Medical School
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Chen Wang
4Boston Children’s Hospital, Department of Neurology, Harvard Medical School
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Qiurui Zeng
1Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School
2Blavatnik Institute, Department of Genetics, Harvard Medical School
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Doudou Yu
1Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School
2Blavatnik Institute, Department of Genetics, Harvard Medical School
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Michael S. Bonkowski
1Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School
2Blavatnik Institute, Department of Genetics, Harvard Medical School
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Jae-Hyun Yang
1Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School
2Blavatnik Institute, Department of Genetics, Harvard Medical School
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Emma M. Hoffmann
3Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School
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Songlin Zhou
4Boston Children’s Hospital, Department of Neurology, Harvard Medical School
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Ekaterina Korobkina
3Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School
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Noah Davidsohn
2Blavatnik Institute, Department of Genetics, Harvard Medical School
6Wyss Institute for Biologically Inspired Engineering, Harvard University
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Michael B. Schultz
1Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School
2Blavatnik Institute, Department of Genetics, Harvard Medical School
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Karolina Chwalek
1Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School
2Blavatnik Institute, Department of Genetics, Harvard Medical School
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Luis A. Rajman
1Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School
2Blavatnik Institute, Department of Genetics, Harvard Medical School
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George M. Church
2Blavatnik Institute, Department of Genetics, Harvard Medical School
6Wyss Institute for Biologically Inspired Engineering, Harvard University
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Konrad Hochedlinger
7Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital
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Vadim N. Gladyshev
5Division of Genetics, Dept. of Medicine, Brigham and Women’s Hospital, Harvard Medical School
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Steve Horvath
8Human Genetics, David Geffen School of Medicine, UCLA
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Meredith S. Gregory-Ksander
3Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School
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Bruce R. Ksander
3Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School
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Zhigang He
4Boston Children’s Hospital, Department of Neurology, Harvard Medical School
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David A. Sinclair
1Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School
2Blavatnik Institute, Department of Genetics, Harvard Medical School
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  • For correspondence: david_sinclair@hms.harvard.edu
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Abstract

Ageing is a degenerative process leading to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage1–3. Changes to DNA methylation patterns over time form the basis of an ‘ageing clock’4, 5, but whether old individuals retain information to reset the clock and, if so, whether this would improve tissue function is not known. Of all the tissues in the body, the central nervous system (CNS) is one of the first to lose regenerative capacity6, 7. Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. This process, which we call recovery of information via epigenetic reprogramming or REVIVER, requires the DNA demethylases Tet1 and Tet2, indicating that DNA methylation patterns don’t just indicate age, they participate in ageing. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal.

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  • ↵* Senior authors;

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Posted July 31, 2019.
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Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming
Yuancheng Lu, Anitha Krishnan, Benedikt Brommer, Xiao Tian, Margarita Meer, Daniel L. Vera, Chen Wang, Qiurui Zeng, Doudou Yu, Michael S. Bonkowski, Jae-Hyun Yang, Emma M. Hoffmann, Songlin Zhou, Ekaterina Korobkina, Noah Davidsohn, Michael B. Schultz, Karolina Chwalek, Luis A. Rajman, George M. Church, Konrad Hochedlinger, Vadim N. Gladyshev, Steve Horvath, Meredith S. Gregory-Ksander, Bruce R. Ksander, Zhigang He, David A. Sinclair
bioRxiv 710210; doi: https://doi.org/10.1101/710210
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Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming
Yuancheng Lu, Anitha Krishnan, Benedikt Brommer, Xiao Tian, Margarita Meer, Daniel L. Vera, Chen Wang, Qiurui Zeng, Doudou Yu, Michael S. Bonkowski, Jae-Hyun Yang, Emma M. Hoffmann, Songlin Zhou, Ekaterina Korobkina, Noah Davidsohn, Michael B. Schultz, Karolina Chwalek, Luis A. Rajman, George M. Church, Konrad Hochedlinger, Vadim N. Gladyshev, Steve Horvath, Meredith S. Gregory-Ksander, Bruce R. Ksander, Zhigang He, David A. Sinclair
bioRxiv 710210; doi: https://doi.org/10.1101/710210

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