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Reprogramming to recover youthful epigenetic information and restore vision

Author

Listed:
  • Yuancheng Lu

    (Harvard Medical School)

  • Benedikt Brommer

    (Harvard Medical School
    Harvard Medical School)

  • Xiao Tian

    (Harvard Medical School)

  • Anitha Krishnan

    (Harvard Medical School
    Harvard Medical School)

  • Margarita Meer

    (Harvard Medical School
    Yale School of Medicine)

  • Chen Wang

    (Harvard Medical School
    Harvard Medical School)

  • Daniel L. Vera

    (Harvard Medical School)

  • Qiurui Zeng

    (Harvard Medical School)

  • Doudou Yu

    (Harvard Medical School)

  • Michael S. Bonkowski

    (Harvard Medical School)

  • Jae-Hyun Yang

    (Harvard Medical School)

  • Songlin Zhou

    (Harvard Medical School
    Harvard Medical School)

  • Emma M. Hoffmann

    (Harvard Medical School
    Harvard Medical School)

  • Margarete M. Karg

    (Harvard Medical School
    Harvard Medical School)

  • Michael B. Schultz

    (Harvard Medical School)

  • Alice E. Kane

    (Harvard Medical School)

  • Noah Davidsohn

    (Harvard University)

  • Ekaterina Korobkina

    (Harvard Medical School
    Harvard Medical School)

  • Karolina Chwalek

    (Harvard Medical School)

  • Luis A. Rajman

    (Harvard Medical School)

  • George M. Church

    (Harvard University)

  • Konrad Hochedlinger

    (Massachusetts General Hospital)

  • Vadim N. Gladyshev

    (Harvard Medical School)

  • Steve Horvath

    (University of California Los Angeles)

  • Morgan E. Levine

    (Yale School of Medicine)

  • Meredith S. Gregory-Ksander

    (Harvard Medical School
    Harvard Medical School)

  • Bruce R. Ksander

    (Harvard Medical School
    Harvard Medical School)

  • Zhigang He

    (Harvard Medical School
    Harvard Medical School)

  • David A. Sinclair

    (Harvard Medical School
    The University of New South Wales)

Abstract

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.

Suggested Citation

  • Yuancheng Lu & Benedikt Brommer & Xiao Tian & Anitha Krishnan & Margarita Meer & Chen Wang & Daniel L. Vera & Qiurui Zeng & Doudou Yu & Michael S. Bonkowski & Jae-Hyun Yang & Songlin Zhou & Emma M. Ho, 2020. "Reprogramming to recover youthful epigenetic information and restore vision," Nature, Nature, vol. 588(7836), pages 124-129, December.
    • Handle: RePEc:nat:nature:v:588:y:2020:i:7836:d:10.1038_s41586-020-2975-4
    DOI: 10.1038/s41586-020-2975-4
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    Citations

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    Cited by:

    1. Albert Stuart Reece & Gary Kenneth Hulse, 2023. "Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration," IJERPH, MDPI, vol. 20(4), pages 1-24, February.
    2. Albert Stuart Reece & Gary Kenneth Hulse, 2022. "Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study," IJERPH, MDPI, vol. 19(13), pages 1-27, June.
    3. Jamie L. Endicott & Paula A. Nolte & Hui Shen & Peter W. Laird, 2022. "Cell division drives DNA methylation loss in late-replicating domains in primary human cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Albert Stuart Reece & Gary Kenneth Hulse, 2022. "Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis," IJERPH, MDPI, vol. 19(24), pages 1-57, December.
    5. Noemie Vilallongue & Julia Schaeffer & Anne-Marie Hesse & Céline Delpech & Béatrice Blot & Antoine Paccard & Elise Plissonnier & Blandine Excoffier & Yohann Couté & Stephane Belin & Homaira Nawabi, 2022. "Guidance landscapes unveiled by quantitative proteomics to control reinnervation in adult visual system," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    6. Ali Doğa Yücel & Vadim N. Gladyshev, 2024. "The long and winding road of reprogramming-induced rejuvenation," Nature Communications, Nature, vol. 15(1), pages 1-9, December.

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