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Reprogramming to recover youthful epigenetic information and restore vision

机译：重新编程以恢复青年表观遗传信息和恢复愿景

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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.
机译：老化是一种退行性过程，导致组织功能障碍和死亡。提出的老化原因是扰乱基因表达模式的表观遗传噪声的积累，导致组织功能和再生能力（1-3）降低。随着时间的推移，DNA甲基化模式的变化形成老化时钟（4）的基础，但老年人是否保留恢复这些模式所需的信息 - 并且如果是这样，这是否可以改善组织函数 - 是不知道的。随着时间的推移，中枢神经系统（CNS）失去功能和再生能力（5-7）。使用眼睛作为模型CNS组织，在此表明OCT4（也称为POU5F1），SOX2和KLF4基因（OSK）在小鼠视网膜神经节细胞中的异位表达恢复青少年的DNA甲基化模式和转录om，促进损伤后轴突再生，并在青光眼和老年小鼠中逆转视力丧失。 OSK诱导的OSK诱导在轴突再生和视觉中进行重编程的有益效果需要DNA去甲基酶TET1和TET2。这些数据表明，哺乳动物组织通过DNA甲基化保留了部分细胞的表观遗传信息编码的记录 - 可以进入改善组织功能并促进体内的再生。小鼠视网膜神经节细胞中的三个yamanaka转录因子的表达恢复青少年甲基化模式，促进损伤后的轴突再生，并逆转青光眼小鼠模型和老年小鼠的视力丧失，表明哺乳动物组织保留了可以访问的年轻表观信息信息，以改善组织功能。

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  • 来源
    《Nature》 |2020年第7836期|124-129|共6页
  • 作者

    Lu Yuancheng; Brommer Benedikt; Tian Xiao; Krishnan Anitha; Meer Margarita; Wang Chen; Vera Daniel L.; Zeng Qiurui; Yu Doudou; Bonkowski Michael S.; Yang Jae-Hyun; Zhou Songlin; Hoffmann Emma M.; Karg Margarete M.; Schultz Michael B.; Kane Alice E.; Davidsohn Noah; Korobkina Ekaterina; Chwalek Karolina; Rajman Luis A.; Church George M.; Hochedlinger Konrad; Gladyshev Vadim N.; Horvath Steve; Levine Morgan E.; Gregory-Ksander Meredith S.; Ksander Bruce R.; He Zhigang; Sinclair David A.;

  • 作者单位

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA;

    Harvard Med Sch Boston Childrens Hosp Dept Neurol Boston MA 02115 USA|Harvard Med Sch Dept Ophthalmol Boston MA 02115 USA;

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA;

    Harvard Med Sch Dept Ophthalmol Boston MA 02115 USA|Harvard Med Sch Schepens Eye Res Inst Mass Eye & Ear Boston MA 02115 USA;

    Harvard Med Sch Dept Med Div Genet Brigham & Womens Hosp Boston MA 02115 USA|Yale Sch Med Dept Pathol New Haven CT USA;

    Harvard Med Sch Boston Childrens Hosp Dept Neurol Boston MA 02115 USA|Harvard Med Sch Dept Ophthalmol Boston MA 02115 USA;

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA;

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA;

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA;

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA;

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA;

    Harvard Med Sch Boston Childrens Hosp Dept Neurol Boston MA 02115 USA|Harvard Med Sch Dept Ophthalmol Boston MA 02115 USA;

    Harvard Med Sch Dept Ophthalmol Boston MA 02115 USA|Harvard Med Sch Schepens Eye Res Inst Mass Eye & Ear Boston MA 02115 USA;

    Harvard Med Sch Dept Ophthalmol Boston MA 02115 USA|Harvard Med Sch Schepens Eye Res Inst Mass Eye & Ear Boston MA 02115 USA;

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA;

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA;

    Harvard Univ Dept Genet Wyss Inst Biol Inspired Engn Boston MA 02115 USA;

    Harvard Med Sch Dept Ophthalmol Boston MA 02115 USA|Harvard Med Sch Schepens Eye Res Inst Mass Eye & Ear Boston MA 02115 USA;

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA;

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA;

    Harvard Univ Dept Genet Wyss Inst Biol Inspired Engn Boston MA 02115 USA;

    Massachusetts Gen Hosp Dept Mol Biol Canc Ctr Boston MA 02114 USA|Massachusetts Gen Hosp Ctr Regenerat Med Boston MA 02114 USA;

    Harvard Med Sch Dept Med Div Genet Brigham & Womens Hosp Boston MA 02115 USA;

    Univ Calif Los Angeles David Geffen Sch Med Dept Human Genet Los Angeles CA 90095 USA;

    Yale Sch Med Dept Pathol New Haven CT USA;

    Harvard Med Sch Dept Ophthalmol Boston MA 02115 USA|Harvard Med Sch Schepens Eye Res Inst Mass Eye & Ear Boston MA 02115 USA;

    Harvard Med Sch Dept Ophthalmol Boston MA 02115 USA|Harvard Med Sch Schepens Eye Res Inst Mass Eye & Ear Boston MA 02115 USA;

    Harvard Med Sch Boston Childrens Hosp Dept Neurol Boston MA 02115 USA|Harvard Med Sch Dept Ophthalmol Boston MA 02115 USA;

    Harvard Med Sch Paul F Glenn Ctr Biol Aging Res Dept Genet Blavatn Inst Boston MA 02115 USA|Univ New South Wares Sch Med Sci Dept Pharmacol Lab Ageing Res Sydney NSW Australia;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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