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Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis

Author

Listed:
  • Liping Deng

    (Institute of Biophysics, Chinese Academy of Sciences
    Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Ruotong Ren

    (Institute of Biophysics, Chinese Academy of Sciences)

  • Zunpeng Liu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Moshi Song

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Jingyi Li

    (Institute of Biophysics, Chinese Academy of Sciences
    Xuanwu Hospital Capital Medical University)

  • Zeming Wu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xiaoqing Ren

    (Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Lina Fu

    (Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Wei Li

    (Xuanwu Hospital Capital Medical University)

  • Weiqi Zhang

    (Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences
    Xuanwu Hospital Capital Medical University)

  • Pedro Guillen

    (Clinica Cemtro. Av. del Ventisquero de la Condesa, 42)

  • Juan Carlos Izpisua Belmonte

    (Salk Institute for Biological Studies)

  • Piu Chan

    (Xuanwu Hospital Capital Medical University)

  • Jing Qu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Guang-Hui Liu

    (Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences
    Xuanwu Hospital Capital Medical University)

Abstract

DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and attenuating aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its microRNA-processing activity. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1γ. Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathologically and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and mouse osteoarthritis. Taken together, these analyses uncovered a novel, microRNA processing-independent role in maintaining heterochromatin organization and attenuating senescence by DGCR8, thus representing a new therapeutic target for alleviating human aging-related disorders.

Suggested Citation

  • Liping Deng & Ruotong Ren & Zunpeng Liu & Moshi Song & Jingyi Li & Zeming Wu & Xiaoqing Ren & Lina Fu & Wei Li & Weiqi Zhang & Pedro Guillen & Juan Carlos Izpisua Belmonte & Piu Chan & Jing Qu & Guang, 2019. "Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10831-8
    DOI: 10.1038/s41467-019-10831-8
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    Cited by:

    1. Matvei Khoroshkin & Andrey Buyan & Martin Dodel & Albertas Navickas & Johnny Yu & Fathima Trejo & Anthony Doty & Rithvik Baratam & Shaopu Zhou & Sean B. Lee & Tanvi Joshi & Kristle Garcia & Benedict C, 2024. "Systematic identification of post-transcriptional regulatory modules," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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