CBX4維持核仁穩(wěn)態(tài)減輕衰老和骨關(guān)節(jié)炎

2019年3月，中國(guó)科學(xué)院生物物理研究所，中國(guó)科學(xué)院生物大分子**研究中心，生物大分子國(guó)家實(shí)驗(yàn)室；中國(guó)科學(xué)院動(dòng)物研究所干細(xì)胞與生殖生物學(xué)國(guó)家重點(diǎn)實(shí)驗(yàn)室；中國(guó)科學(xué)院大學(xué)；北京大學(xué)生命科學(xué)學(xué)院生物動(dòng)力光學(xué)成像中心；中國(guó)科學(xué)院動(dòng)物研究所膜生物學(xué)國(guó)家重點(diǎn)實(shí)驗(yàn)室；中國(guó)科學(xué)院干細(xì)胞與再生研究所；

首都醫(yī)科大學(xué)宣武醫(yī)院國(guó)家老年疾病臨床研究中心，人腦保護(hù)先進(jìn)創(chuàng)新中心；解放軍第306醫(yī)院陸軍口腔疾病診療中心；北京大學(xué)基礎(chǔ)醫(yī)學(xué)院生理與病理生理教研室，心血管分子科學(xué)教育部重點(diǎn)實(shí)驗(yàn)室，心血管受體研究北京市重點(diǎn)實(shí)驗(yàn)室；中國(guó)科學(xué)院生物物理研究所，中國(guó)科學(xué)院生物大分子**研究中心，RNA生物學(xué)重點(diǎn)實(shí)驗(yàn)室；北京大學(xué)北大-清華生命科學(xué)研究中心；細(xì)胞增殖與分化教育部重點(diǎn)實(shí)驗(yàn)室；北京大學(xué)生物醫(yī)學(xué)前沿融合研究研究所；首都醫(yī)科大學(xué)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(tuán)隊(duì)在《Cell Reports》上，發(fā)表論文為：“Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis

”

“CBX4維持核仁穩(wěn)態(tài)減輕衰老和骨關(guān)節(jié)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(fù)合體1 (polycomb repression complex 1, PRC1)的一個(gè)組成部分，通過(guò)基因沉默在維持細(xì)胞身份和器官發(fā)育中發(fā)揮重要作用。然而，CBX4是否調(diào)節(jié)人類干細(xì)胞穩(wěn)態(tài)仍不清楚。在這里，我們證明CBX4通過(guò)維持核仁穩(wěn)態(tài)來(lái)抵消人間充質(zhì)干細(xì)胞(hMSC)的衰老。CBX4蛋白在衰老的hMSCs中下調(diào)，而在hMSCs中敲除CBX4導(dǎo)致核仁異染色質(zhì)不穩(wěn)定，核糖體生物發(fā)生增強(qiáng)，蛋白質(zhì)翻譯增加，細(xì)胞衰老加速。CBX4通過(guò)在核仁rDNA上募集核仁蛋白纖維蛋白(FBL)和異染色質(zhì)蛋白krab相關(guān)蛋白1 (KAP1)來(lái)維持核仁穩(wěn)態(tài)，限制rnas的過(guò)度表達(dá)。CBX4過(guò)表達(dá)可緩解小鼠hMSC生理性老化，減輕骨關(guān)節(jié)炎的發(fā)生。總之，我們的研究結(jié)果揭示了CBX4通過(guò)維持核核穩(wěn)態(tài)來(lái)對(duì)抗細(xì)胞衰老的關(guān)鍵作用，為衰老相關(guān)疾病提供了潛在的治療靶點(diǎn)。

該論文中，H9 hESCs細(xì)胞的體外培養(yǎng)是使用Ausbian特級(jí)胎牛血清完成的。欲了解或購(gòu)買(mǎi)Ausbian特級(jí)胎牛血清可以聯(lián)系北京締一生物400-166-8600.