Reprogramming to recover youthful epigenetic information and restore vision

被引:516
作者
Lu, Yuancheng [1 ]
Brommer, Benedikt [2 ,3 ]
Tian, Xiao [1 ]
Krishnan, Anitha [3 ,4 ]
Meer, Margarita [5 ,6 ]
Wang, Chen [2 ,3 ]
Vera, Daniel L. [1 ]
Zeng, Qiurui [1 ]
Yu, Doudou [1 ]
Bonkowski, Michael S. [1 ]
Yang, Jae-Hyun [1 ]
Zhou, Songlin [2 ,3 ]
Hoffmann, Emma M. [3 ,4 ]
Karg, Margarete M. [3 ,4 ]
Schultz, Michael B. [1 ]
Kane, Alice E. [1 ]
Davidsohn, Noah [7 ]
Korobkina, Ekaterina [3 ,4 ]
Chwalek, Karolina [1 ]
Rajman, Luis A. [1 ]
Church, George M. [7 ]
Hochedlinger, Konrad [8 ,9 ]
Gladyshev, Vadim N. [5 ]
Horvath, Steve [10 ]
Levine, Morgan E. [6 ]
Gregory-Ksander, Meredith S. [3 ,4 ]
Ksander, Bruce R. [3 ,4 ]
He, Zhigang [2 ,3 ]
Sinclair, David A. [1 ,11 ]
机构
[1] Harvard Med Sch, Paul F Glenn Ctr Biol Aging Res, Dept Genet, Blavatn Inst, Boston, MA 02115 USA
[2] Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA
[3] Harvard Med Sch, Dept Ophthalmol, Boston, MA 02115 USA
[4] Harvard Med Sch, Schepens Eye Res Inst Mass Eye & Ear, Boston, MA 02115 USA
[5] Harvard Med Sch, Dept Med, Div Genet, Brigham & Womens Hosp, Boston, MA 02115 USA
[6] Yale Sch Med, Dept Pathol, New Haven, CT USA
[7] Harvard Univ, Dept Genet, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA
[8] Massachusetts Gen Hosp, Dept Mol Biol, Canc Ctr, Boston, MA 02114 USA
[9] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA
[10] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA
[11] Univ New South Wales, Sch Med Sci, Dept Pharmacol, Lab Ageing Res, Sydney, NSW, Australia
关键词
ACTIVE DNA DEMETHYLATION; AXON REGENERATION; GENE-EXPRESSION; AGE; METHYLATION; LONGEVITY; CELLS; TET1; HALLMARKS; GLAUCOMA;
D O I
10.1038/s41586-020-2975-4
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 capacity(1-3). Changes to DNA methylation patterns over time form the basis of ageing clocks(4), 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 capacity(5-7). 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.
引用
收藏
页码:124 / 129
页数:6
相关论文
共 71 条
[1]   Reprogramming in vivo produces teratomas and iPS cells with totipotency features [J].
Abad, Maria ;
Mosteiro, Lluc ;
Pantoja, Cristina ;
Canamero, Marta ;
Rayon, Teresa ;
Ors, Inmaculada ;
Grana, Osvaldo ;
Megias, Diego ;
Dominguez, Orlando ;
Martinez, Dolores ;
Manzanares, Miguel ;
Ortega, Sagrario ;
Serrano, Manuel .
NATURE, 2013, 502 (7471) :340-+
[2]  
Almasieh M, 2016, ANNU REV VIS SCI, V3, P1
[3]   Gene Ontology: tool for the unification of biology [J].
Ashburner, M ;
Ball, CA ;
Blake, JA ;
Botstein, D ;
Butler, H ;
Cherry, JM ;
Davis, AP ;
Dolinski, K ;
Dwight, SS ;
Eppig, JT ;
Harris, MA ;
Hill, DP ;
Issel-Tarver, L ;
Kasarskis, A ;
Lewis, S ;
Matese, JC ;
Richardson, JE ;
Ringwald, M ;
Rubin, GM ;
Sherlock, G .
NATURE GENETICS, 2000, 25 (01) :25-29
[4]  
Bar-Nur O, 2014, NAT METHODS, V11, P1170, DOI [10.1038/nmeth.3142, 10.1038/NMETH.3142]
[5]   The Gene Ontology Resource: 20 years and still GOing strong [J].
Carbon, S. ;
Douglass, E. ;
Dunn, N. ;
Good, B. ;
Harris, N. L. ;
Lewis, S. E. ;
Mungall, C. J. ;
Basu, S. ;
Chisholm, R. L. ;
Dodson, R. J. ;
Hartline, E. ;
Fey, P. ;
Thomas, P. D. ;
Albou, L. P. ;
Ebert, D. ;
Kesling, M. J. ;
Mi, H. ;
Muruganujian, A. ;
Huang, X. ;
Poudel, S. ;
Mushayahama, T. ;
Hu, J. C. ;
LaBonte, S. A. ;
Siegele, D. A. ;
Antonazzo, G. ;
Attrill, H. ;
Brown, N. H. ;
Fexova, S. ;
Garapati, P. ;
Jones, T. E. M. ;
Marygold, S. J. ;
Millburn, G. H. ;
Rey, A. J. ;
Trovisco, V. ;
dos Santos, G. ;
Emmert, D. B. ;
Falls, K. ;
Zhou, P. ;
Goodman, J. L. ;
Strelets, V. B. ;
Thurmond, J. ;
Courtot, M. ;
Osumi-Sutherland, D. ;
Parkinson, H. ;
Roncaglia, P. ;
Acencio, M. L. ;
Kuiper, M. ;
Laegreid, A. ;
Logie, C. ;
Lovering, R. C. .
NUCLEIC ACIDS RESEARCH, 2019, 47 (D1) :D330-D338
[6]   AmiGO: online access to ontology and annotation data [J].
Carbon, Seth ;
Ireland, Amelia ;
Mungall, Christopher J. ;
Shu, ShengQiang ;
Marshall, Brad ;
Lewis, Suzanna .
BIOINFORMATICS, 2009, 25 (02) :288-289
[7]  
Dordea AC, 2013, EXP EYE RES, V147, P1218
[8]   Preprocessing, normalization and integration of the Illumina HumanMethylationEPIC array with minfi [J].
Fortin, Jean-Philippe ;
Triche, Timothy J., Jr. ;
Hansen, Kasper D. .
BIOINFORMATICS, 2017, 33 (04) :558-560
[9]   Replacement of Oct4 by Tet1 during iPSC Induction Reveals an Important Role of DNA Methylation and Hydroxymethylation in Reprogramming [J].
Gao, Yawei ;
Chen, Jiayu ;
Li, Ke ;
Wu, Tong ;
Huang, Bo ;
Liu, Wenqiang ;
Kou, Xiaochen ;
Zhang, Yu ;
Huang, Hua ;
Jiang, Yonghua ;
Yao, Chao ;
Liu, Xiaolei ;
Lu, Zhiwei ;
Xu, Zijian ;
Kang, Lan ;
Chen, Jun ;
Wang, Hailin ;
Cai, Tao ;
Gao, Shaorong .
CELL STEM CELL, 2013, 12 (04) :453-469
[10]   Evidence for an Age-Dependent Decline in Axon Regeneration in the Adult Mammalian Central Nervous System [J].
Geoffroy, Cedric G. ;
Hilton, Brett J. ;
Tetzlaff, Wolfram ;
Zheng, Binhai .
CELL REPORTS, 2016, 15 (02) :238-246