Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis

被引：95

作者：

Deng, Liping ^{[1
,2
,3
,4
]}

Ren, Ruotong ^{[1
]}

Liu, Zunpeng ^{[2
,4
]}

Song, Moshi ^{[3
,4
,5
]}

Li, Jingyi ^{[1
,6
]}

Wu, Zeming ^{[2
,4
]}

Ren, Xiaoqing ^{[1
,4
]}

Fu, Lina ^{[1
,4
]}

Li, Wei ^{[6
]}

Zhang, Weiqi ^{[1
,4
,5
,6
,7
]}

Guillen, Pedro ^{[8
]}

Belmonte, Juan Carlos Izpisua ^{[9
]}

Chan, Piu ^{[6
]}

Qu, Jing ^{[2
,4
,5
]}

Liu, Guang-Hui ^{[1
,4
,5
,6
,10
,11
]}

机构：

[1] Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing 100101, Peoples R China

[2] Chinese Acad Sci, Inst Zool, State Key Lab Stem Cell & Reprod Biol, Beijing 100101, Peoples R China

[3] Chinese Acad Sci, Inst Zool, State Key Lab Membrane Biol, Beijing 100101, Peoples R China

[4] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[5] Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing 100101, Peoples R China

[6] Capital Med Univ, Xuanwu Hosp, Natl Clin Res Ctr Geriatr Disorders, Adv Innovat Ctr Human Brain Protect, Beijing 100053, Peoples R China

[7] Chinese Acad Sci, Beijing Inst Genom, Key Lab Genom & Precis Med, Beijing 100101, Peoples R China

[8] Clin Cemtro, Av Ventisquero Condesa 42, Madrid 28035, Spain

[9] Salk Inst Biol Studies, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA

[10] Jinan Univ, Inst Aging & Regenerat Med, Key Lab Regenerat Med, Minist Educ, Guangzhou 510632, Guangdong, Peoples R China

[11] Capital Med Univ, Beijing Inst Brain Disorders, Beijing 100069, Peoples R China

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷

基金：

中国国家自然科学基金;

关键词：

MESENCHYMAL STEM-CELLS; REGION; 8; DGCR8; MICRORNA BIOGENESIS; MICROPROCESSOR COMPONENT; READ ALIGNMENT; WERNER; REPAIR; MODEL; VISUALIZATION; METHYLATION;

D O I：

10.1038/s41467-019-10831-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 (DR8(dex2)) 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 HP1 gamma. Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8(dex2) 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.

引用

页数：16

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