Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis

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 () and Guang-Hui Liu ()
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Liping Deng: Institute of Biophysics, Chinese Academy of Sciences
Ruotong Ren: Institute of Biophysics, Chinese Academy of Sciences
Zunpeng Liu: Chinese Academy of Sciences
Moshi Song: Chinese Academy of Sciences
Jingyi Li: Institute of Biophysics, Chinese Academy of Sciences
Zeming Wu: Chinese Academy of Sciences
Xiaoqing Ren: Institute of Biophysics, Chinese Academy of Sciences
Lina Fu: Institute of Biophysics, Chinese Academy of Sciences
Wei Li: Xuanwu Hospital Capital Medical University
Weiqi Zhang: Institute of Biophysics, Chinese Academy of Sciences
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
Guang-Hui Liu: Institute of Biophysics, Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10831-8

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