CBX4維持核仁穩態減輕衰老和骨關節炎

2019年3月，中國科學院生物物理研究所，中國科學院生物大分子**研究中心，生物大分子國家實驗室；中國科學院動物研究所干細胞與生殖生物學國家重點實驗室；中國科學院大學；北京大學生命科學學院生物動力光學成像中心；中國科學院動物研究所膜生物學國家重點實驗室；中國科學院干細胞與再生研究所；

首都醫科大學宣武醫院國家老年疾病臨床研究中心，人腦保護先進創新中心；解放軍第306醫院陸軍口腔疾病診療中心；北京大學基礎醫學院生理與病理生理教研室，心血管分子科學教育部重點實驗室，心血管受體研究北京市重點實驗室；中國科學院生物物理研究所，中國科學院生物大分子**研究中心，RNA生物學重點實驗室；北京大學北大-清華生命科學研究中心；細胞增殖與分化教育部重點實驗室；北京大學生物醫學前沿融合研究研究所；首都醫科大學北京腦疾病研究所；（National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

University of Chinese Academy of Sciences, Beijing 100049, China

Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China

State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China

Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China

Army Diagnosis and Treatment Center for Oral Disease, 306th Hospital of the PLA, Beijing 100101, China

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China

Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences,Beijing 100101, China

Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China

Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China

Biomedical Institute for Pioneering Investigation via Convergence, Peking University, Beijing 100871, China

Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China ） Guang-Hui Liu研究團隊在《Cell Reports》上，發表論文為：“Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis

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“CBX4維持核仁穩態減輕衰老和骨關節炎”

Abstract

CBX4, a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through gene silencing. However, whether CBX4 regulates human stem cell homeostasis remains unclear. Here, we demonstrate that CBX4 counteracts human mesenchymal stem cell (hMSC) aging via the maintenance of nucleolar homeostasis. CBX4 protein is downregulated in aged hMSCs, whereas CBX4 knockout in hMSCs results in destabilized nucleolar heterochromatin, enhanced ribosome biogenesis, increased protein translation, and accelerated cellular senescence. CBX4 maintains nucleolar homeostasis by recruiting nucleolar protein fibrillarin (FBL) and heterochromatin protein KRAB-associated protein 1 (KAP1) at nucleolar rDNA, limiting the excessive expression of rRNAs. Overexpression of CBX4 alleviates physiological hMSC aging and attenuates the development of osteoarthritis in mice. Altogether, our findings reveal a critical role of CBX4 in counteracting cellular senescence by maintaining nucleolar homeostasis, providing a potential therapeutic target for aging-associated disorders.

摘要

CBX4是多梳抑制復合體1 (polycomb repression complex 1, PRC1)的一個組成部分，通過基因沉默在維持細胞身份和器官發育中發揮重要作用。然而，CBX4是否調節人類干細胞穩態仍不清楚。在這里，我們證明CBX4通過維持核仁穩態來抵消人間充質干細胞(hMSC)的衰老。CBX4蛋白在衰老的hMSCs中下調，而在hMSCs中敲除CBX4導致核仁異染色質不穩定，核糖體生物發生增強，蛋白質翻譯增加，細胞衰老加速。CBX4通過在核仁rDNA上募集核仁蛋白纖維蛋白(FBL)和異染色質蛋白krab相關蛋白1 (KAP1)來維持核仁穩態，限制rnas的過度表達。CBX4過表達可緩解小鼠hMSC生理性老化，減輕骨關節炎的發生?？傊?，我們的研究結果揭示了CBX4通過維持核核穩態來對抗細胞衰老的關鍵作用，為衰老相關疾病提供了潛在的治療靶點。

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