Year: 2019
Type: article
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.
Source: Nature Communications
Institutions: Chinese Academy of Sciences, Institute of Biophysics, University of Chinese Academy of Sciences, Institute of Zoology, State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Capital Medical University, Xuan Wu Hospital of the Capital Medical University, Beijing Institute of Genomics, Salk Institute for Biological Studies, Jinan University, Beijing Institute for Brain Disorders
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: G1074237133, G1210379912, G1793612515, G1925184550, G1942136960, 人类成年早衰症模型的建立及其分子机制研究, G2391531473, NF-kB信号通路对人类干细胞稳态与衰老的影响及作用机制, G2679234170, G2947813951, G3080630271, G3274609548, G3283615488, G3283977219, 线粒体质量控制保护心肌缺血再灌注损伤的机制研究, G3956902489, G4017673553, G4116647621, G4193866340, G4575265866, G5228077683, G563050417, G5641816761, G5844530885, G6017193691, G6071137223, G6684708555, G6844520676, G754511529, G7570836684, G7819028244, G8213732483, G8266073478, G837043620, G838822281, G8764340019, G8906294493
OpenAlex ID: W2965494858