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Nat Commun. 2019 Jul 26;10(1):3329. doi: 10.1038/s41467-019-10831-8.

Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis.

Deng L1,2,3,4, Ren R1, Liu Z2,4, Song M3,4,5, Li J1,6, Wu Z2,4, Ren X1,4, Fu L1,4, Li W6, Zhang W1,4,5,6,7, Guillen P8, Izpisua Belmonte JC9, Chan P6, Qu J10,11,12, Liu GH13,14,15,16,17,18.

Author information

1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
2
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China.
3
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China.
4
University of Chinese Academy of Sciences, 100049, Beijing, China.
5
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, China.
6
Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, 100053, Beijing, China.
7
Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, 100101, Beijing, China.
8
Clinica Cemtro. Av. del Ventisquero de la Condesa, 42, 28035, Madrid, Spain.
9
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
10
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China. qujing@ioz.ac.cn.
11
University of Chinese Academy of Sciences, 100049, Beijing, China. qujing@ioz.ac.cn.
12
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, China. qujing@ioz.ac.cn.
13
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China. ghliu@ibp.ac.cn.
14
University of Chinese Academy of Sciences, 100049, Beijing, China. ghliu@ibp.ac.cn.
15
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, China. ghliu@ibp.ac.cn.
16
Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, 100053, Beijing, China. ghliu@ibp.ac.cn.
17
Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, 510632, Guangzhou, China. ghliu@ibp.ac.cn.
18
Beijing Institute for Brain Disorders, Capital Medical University, 100069, Beijing, China. ghliu@ibp.ac.cn.

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.

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