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APOE-mediated suppression of the lncRNA MEG3 protects human cardiovascular cells from chronic inflammation

Protein & Cell 2023年第12期14卷 908-913页

作者： Hongkai Zhao Kuan Yang Yiyuan Zhang Hongyu Li Qianzhao ji Zeming Wu Shuai Ma Si Wang Moshi Song guang-hui liu Qiang liu Weiqi Zhang Jing Qu Division of Life Sciences and Medicine School of Life SciencesUniversity of Science and Technology of ChinaHefei 230001China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Universityof Chinese Academy of Sciences Beijing100049China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical University.Beijing100053China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Aging Biomarker Consortium Beijing 100101China 12Division of Life Sciences and Medicine Institute on Aging and Brain DisordersThe First Affiliated Hospital of USTCHefei National Laboratory for Physical Sciences at the MicroscaleUniversity of Science and Technology of ChinaHefei 230026China Neurodegenerative Disease Research Center University of Science and Technology of ChinaHefei 230026China CAS Key Laboratory of Brain Function and Disease University of Science and Technology of ChinaHefei 230026China Center for Excellence in Animal Evolution and Genetics Chinese Academy of SciencesKunming 650201China

Dear Editor,Cardiovascular diseases(CVDs)are the leading cause of death ***,diagnosing and treating CVD remains at the forefront for clinicians while identifying targetable disease mechanisms in preclinical models are focus areas for researchers and drug developers(Cai et al.,2022a).The polymorphic protein apolipoprotein E(APOE),central to lipid transport and metabolism,is well-recognized for the role of its isoforms as important predictors for human cardiovascular disorders and neurodegenerative diseases(Tudorache et al.,2017).Plasma APOE is generated primarily from liver hepatocytes,accounting for around 75%of the APOE production from the whole body(Getz and Reardon,2009),and plays important functional roles in monocytes/macrophages,adipocytes,and the central nervous system(Kockx et al.,2018).However,despite the fact that APOE is widely expressed in different mammalian cells,studies on the functional roles of APOE mostly focus on its extracellular secreted form,and the specific effects of APOE,particularly intracellular form in cell types closely related to human cardiovascular diseases are therefore still poorly understood.

关键词： cardiovascular metabolism

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ALKBH1 deficiency leads to loss of homeostasis in human diploid somatic cells

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Protein & Cell 2020年第9期11卷 688-695页

作者： Hongyu Li Zeming Wu Xiaoqian liu Sheng Zhang Qianzhao Ji Xiaoyu Jiang Zunpeng liu Si Wang Jing Qu Weiqi Zhang Moshi Song Eli Song guang-hui liu National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China

Dear Editor,As the most prevalent DNA methylation modification in prokaryotes,DNA N6 methyladenosine(6mA)in eukaryotic genomes has recently been observed in diverse species including Caenorhabditis elegans(Greer et al.,2015),Dro-sophila melanogaster(Zhang et al,2015),mouse(Wu et al,2016)and human(Xiao et al,2018).6mA has been reported to associate with multiple physiological processes including embryonic development and tumorigenesis(Greer et al.,2015;Zhang et al.,2015;Xie et al.,2018),yet some con-troversies *** contrast to the findings showing that ALKBH1(alkB homolog 1)is a primary 6mA demethylase in mouse and human cells(Wu et al.,2016;Xiao et al.,2018;Xie et al..2018),other studies indicate that ALKBH1 is prone to demethylate 6mA on bubbled or bulged DNAs that are often featured by a locally unpairing region with flanking duplex,such as D-loop,R-loop as well as DNA or RNA stem-loop,and single-stranded DNAs at a lower efficiency.

关键词： homeostasis bubble pairing

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Single-nucleus transcriptomic landscape of primate hippocampal aging

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Protein & Cell 2021年第9期12卷 695-716页

作者： hui Zhang Jiaming Li Jie Ren Shuhui Sun Shuai Ma Weiqi Zhang Yang Yu Yusheng Cai Kaowen Yan Wei Li Baoyang Hu Piu Chan Guo-guang Zhao Juan Carlos Izpisua Belmonte Qi Zhou Jing Qu Si Wang guang-hui liu State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China China National Center for Bioinformation Beijing 100101China Aging Translational Medicine Center Xuanwu HospitalCapital Medical UniversityBeijing 100053China Department of Neurosurgery Xuanwu HospitalCapital Medical UniversityBeijing 100053China Sino Danish CollegeUniversity of Chinese Academy of SciencesBeijing 101408China Sino Danish Center for Education and ResearchBeijing 101408China Department of Obstetrics and Gynecology Center for Reproductive MedicinePeking University Third HospitalBeijing 100191China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Stem Cell Research Center Peking University Third HospitalBeijing 100191China Gene Expression Laboratory Salk Institute for Biological StudiesLa JollaCAUSA

The hippocampus plays a crucial role in learning and memory,and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative *** a systematic profiling of the aging effects on various hippocampal cell types in primates is still ***,we reported a variety of new aging-associated phenotypic changes of the primate *** include,in particular,increased DNA damage and heterochromatin erosion with time,alongside loss of proteostasis and elevated *** understand their cellular and molecular causes,we established the first single-nucleus transcriptomic atlas of primate hippocampal *** the 12 identified cell types,neural transiently amplifying progenitor cell(TAPC)and microglia were most affected by ***-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory;additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte,as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for *** rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

关键词： aging hippocampus primate single-cell RNA sequencing

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DJ-1 is dispensable for human stem cell homeostasis

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Protein & Cell 2019年第11期10卷 846-853页

作者： Fang Cheng Si Wang Moshi Song Zunpeng liu Ping liu Lei Wang Yanjiang Wang Qian Zhao Kaowen Yan Piu Chan Weiqi Zhang Jing Qu guang-hui liu National Laboratory of Biomacromolecules CAS Center for Excellenee in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Advaneed Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China Department of Neurology Daping HospitalThird Military Medical UniversityChongqing 400042China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem cell and Regeneration Chinese Academy of SciencesBeijing 100101China Translational Medical Center for Stem Cell Therapy Shanghai East HospitalTongji University School of MedicineShanghai 200120China

Dear Editor,Safeguard!ng cellular redox homeostasis is crucial for maintaining organism health and preventing *** stress,often characterized by decreased mitochondrial integrity and increased reactive oxygen species(ROS)product!on,disrupts proteostasis and genomic stability,which may eventually lead to cellular decomposition(Oh et al.,2014).Stem cells(such as mesenchymal stem cells,MSCs,and neural stem cells,NSCs)are susceptible to various external and internal stresses,and their dysfunction con tributes to aging and agin g-related ***,it is of importance to elucidate the complex signaling networks regulated by oxidative stress in stem *** redox signaling has been implicated in multiple cellular processes,how the redox system functions in various human stem cells is unclear.

关键词： PARKINSONS-DISEASE CHCHD2 MUTATIONS REGULATOR

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Telomere-dependent and telomereindependent roles of RAP1 in regulating human stem cell homeostasis

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Protein & Cell 2019年第9期10卷 649-667页

作者： Xing Zhang Zunpeng liu Xiaoqian liu Si Wang Yiyuan Zhang Xiaojuan He Shuhui Sun Shuai Ma Ng Shyh-Chang Feng liu Qiang Wang Xiaoqun Wang Lin liu Weiqi Zhang Moshi Song guang-hui liu Jing Qu State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of Sciences Beijing 100101China Advaneed Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China National Laboratory of Biomacromolecules CAS Center for Excellenee in BiomacromoleculesInstitute of Biophysics Chinese Academy of SciencesBeijing 100101China State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjin 300071China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem cell and Regeneration Chinese Academy of SciencesBeijing 100101China Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative MedicineJinan UniversityGuangzhou 510632China Beijing Institute for Brain Disorders Capital Medical UniversityBeijing 100069China

RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclea匚 Here we generated RAP1 -deficient human embryonic stem cells (hESCs) by using CRISPR/Cas9 technique and obtained RAP1-deficient human mesenchymal stem cells (hMSCs) and neural stem cells (hNSCs) via directed differentiation. In both hMSCs and hNSCs, RAP1 not only negatively regulated telomere length but also acted as a transcriptional regulator of RELN by tuning the methylation status of its gene promoter. RAP1 deficiency enhanced self-renewal and delayed senescence in hMSCs, but not in hNSCs, suggesting complicated lineage-specific effects of RAP1 in adult stem ***, these results demonstrate for the first time that RAP1 plays both telomeric and nontelomeric roles in regulating human stem cell homeostasis.

关键词： RAP1 stem cell telomere RELN methylation

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A single-cell transcriptomic atlas of primate pancreatic islet aging

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National Science Review 2021年第2期8卷 17-31页

作者： Jingyi Li Yuxuan Zheng Pengze Yan Moshi Song Si Wang Liang Sun Zunpeng liu Shuai Ma Juan Carlos Izpisua Belmonte Piu Chan Qi Zhou Weiqi Zhang guang-hui liu Fuchou Tang Jing Qu State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of Sciences National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of Sciences Beijing Institute for Brain Disorders Advanced Innovation Center for Human Brain ProtectionNational Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical University University of Chinese Academy of Sciences Beijing Advanced Innovation Center for Genomics Biomedical Pioneering Innovation CenterCollege of Life SciencesPeking University Ministry of Education Key Laboratory of Cell Proliferation and Differentiation Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking University Institute for Stem Cell and Regeneration Chinese Academy of Sciences The MOH Key Laboratory of Geriatrics Beijing HospitalNational Center of Gerontology State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of Sciences Gene Expression Laboratory Salk Institute for Biological Studies CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences China National Center for Bioinformation

Aging-related degeneration of pancreatic islet cells contributes to impaired glucose tolerance and *** cells age heterogeneously, complicating the efforts to unravel the molecular drivers underlying endocrine aging. To overcome these obstacles, we undertook single-cell RNA sequencing of pancreatic islet cells obtained from young and aged non-diabetic cynomolgus monkeys. Despite sex differences and increased transcriptional variations, aged β-cells showed increased unfolded protein response(UPR) along with the accumulation of protein aggregates. We observed transcriptomic dysregulation of UPR components linked to canonical ATF6 and IRE1 signaling pathways, comprising adaptive UPR during pancreatic aging. Notably, we found aging-related β-cell-specific upregulation of HSP90 B1, an endoplasmic reticulum-located chaperone, impeded high glucose-induced insulin secretion. Our work decodes aging-associated transcriptomic changes that underlie pancreatic islet functional decay at single-cell resolution and indicates that targeting UPR components may prevent loss of proteostasis,suggesting an avenue to delaying β-cell aging and preventing aging-related diabetes.

关键词： islet β-cell aging single-cell RNA sequencing primate

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Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells

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Protein & Cell 2019年第4期10卷 249-271页

作者： Chen Ling Zunpeng liu Moshi Song Weiqi Zhang Si Wang Xiaoqian liu Shuai Ma Shuhui Sun Lina Fu Qun Chu Juan Carlos Izpisua Belmonte Zhaoxia Wang Jing Qu Yun Yuan guang-hui liu Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China Beijing Institute for Brain Disorders Capital Medical UniversityBeijing 100069China Department of Neurology Peking University First HospitalBeijing 100034China National Laboratory of Biomacromolecules CAS Center for Excellenee in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Gene Expression Laboratory Salk Institute for Biological Studies10010 North Torrey Pines RoadLa JollaCA 92037USA Institute for Stem cell and Regeneration CASBeijing 100101China Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative MedicineJinan UniversityGuangzhou 510632China

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is a rare hereditary cerebrovascular disease caused by a NOTCH3 ***,the underlying cellular and molecular mechanisms remain ***,we generated non-integrative induced pluripotent stem cells(iPSCs)from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation(c.3226C>T,p.R1076C).Vascular smooth muscle cells(VSMCs)differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes,including activation of the NOTCH and NF-kB signaling pathway,cytoskeleton disorganization,and excessive cell *** comparison,these abnormalities were not observed in vascular endothelial cells(VECs)derived from the patients ***,the abnormal upregulation of NF-kB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor,providing a potential therapeutic strategy for ***,using this iPSCbased disease model,our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.

关键词： CADASIL iPSC NOTCH NF-kB vascular smooth muscle

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Single-cell profiling reveals a potent role of quercetin in promoting hair regeneration

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Protein & Cell 2023年第6期14卷 398-415页

作者： Qian Zhao Yandong Zheng Dongxin Zhao Liyun Zhao Lingling Geng Shuai Ma Yusheng Cai Chengyu liu Yupeng Yan Juan Carlos Izpisua Belmonte Si Wang Weiqi Zhang guang-hui liu Jing Qu Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuan Wu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciencesand China National Center for BioinformationBeijing 100101China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China The Fifth People's Hospital of Chongqing Chongqing 400062China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China Altos Labs Inc.San DiegoCA 94022USA

Hair loss affects millions of people at some time in their life,and safe and efficient treatments for hair loss are a significant unmet medical *** report that topical delivery of quercetin(Que)stimulates resting hair follicles to grow with rapid follicular keratinocyte proliferation and replenishes perifollicular microvasculature in *** construct dynamic single-cell transcriptome landscape over the course of hair regrowth and find that Que treatment stimulates the differentiation trajectory in the hair follicles and induces an angiogenic signature in dermal endothelial cells by activating HIF-1αin endothelial *** administration of a HIF-1αagonist partially recapitulates the pro-angiogenesis and hair-growing effects of ***,these findings provide a molecular understanding for the efficacy of Que in hair regrowth,which underscores the translational potential of targeting the hair follicle niche as a strategy for regenerative medicine,and suggest a route of pharmacological intervention that may promote hair regrowth.

关键词： single-cell RNA-sequencing Que hair follicle regeneration endothelial cells HIF-1α

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CRISPR-based screening identifies XPO7 as a positive regulatorof senescence

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蛋白质与细胞:英文版 2023年第8期14卷 623-628页

作者： Lan-Zhu Li Kuan Yang Yaobin Jing Yanling Fan Xiaoyu Jiang Si Wang guang-hui liu Jing Qu Shuai Ma Weiqi Zhang State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing100101China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China School of Future Technology University of Chinese Academy of SciencesBeijing 100190China Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China

Dear Editor,Cells enter senescence,or irreversible growth arrest,when exposed to stressors such as DNA damage,epigenetic alterations and chronic inflammation(Zhao and Chen,2022).In aging and aging-related diseases,sen... 详细信息

关键词： alterations organs

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Deciphering primate retinal aging at single-cell resolution

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Protein & Cell 2021年第11期12卷 889-898页

作者： Si Wang Yuxuan Zheng Qingqing Li Xiaojuan He Ruotong Ren Weiqi Zhang Moshi Song huifang Hu Feifei liu Guoqiang Sun Shuhui Sun Zunpeng liu Yang Yu Piu Chan Guo-guang Zhao Qi Zhou guang-hui liu Fuchou Tang Jing Qu State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Beijing Advanced Innovation Center for Genomics School of Life SciencesPeking UniversityBeijing 100871China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China Institute for Stem Cell and Regeneration CASBeijing 100101China Ministry of Education Key Laboratory of Cell Proliferation and Differentiation Biomedical Pioneering Innovation CenterBeijing 100871China Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100871China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China Disease Genomics and Individualized Medicine Laboratory Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China Department of Obstetrics and Gynecology Center for Reproductive MedicinePeking University Third HospitalBeijing 100191China Stem Cell Research Center Peking University Third HospitalBeijing 100191China Department of Neurosurgery Xuanwu HospitalCapital Medical UniversityBeijing 100053China

Dear Editor, The retina is a light-sensitive highly-organized tissue,which is vulnerable to aging and age-related retinal ***,progressive retinal degeneration leads to visual function deterioration and vision impairment in the elderly(Lin et al.,2016).In diseases such as age-related macular degeneration(AMD),retinitis pigmentosa(RP)and diabetic retinopathy(DR),pathological process lacking effective treatments profoundly and negatively impact on the quality of life in the elderly(Lin et al.,2016;Chen et al.,2019).Thus,an in-depth molecular assessment of the mechanisms driv-ing retinal aging is of urgent scientific and medical importance.

关键词： degeneration aging resolution

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