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MAVS Antagonizes Human Stem Cell Senescence as a Mitochondrial Stabilizer

Research 2024年第2期2023卷 239-257页

作者： Cui Wang Kuan Yang Xiaoqian Liu Si Wang Moshi Song Juan Carlos Izpisua Belimonte Jing Qu Guang-Hui Liu Weiqi Zhang CAS Key Laboratory of Genomic and Precision Medicine Beijng Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of Sciences Beijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Bejing 100101China Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Altos Labs Inc.San DiegoCA 94022USA

Mitochondrial dysfunction is a hallmark feature of cellular senescence and organ ***,we asked whether the mitochondrial antiviral signaling protein(MAVS),which is essential for driving antiviral response,also regulates human stem cell *** answer this question,we used CRISPR/Cas9-mediated gene editing and directed differentiation techniques to generate various MAVS-knockout human stem cell *** found that human mesenchymal stem cells(hMSCs)were sensitive to MAVS deficiency,as manifested by accelerated senescence *** uncovered that the role of MAVS in maintaining mitochondrial structural integrity and functional homeostasis depends on its interaction with the guanosine triphosphatase optic atrophy type 1(OPA1).Depletion of MAVS or OPA1 led to the dysfunction of mitochondria and cellular senescence,whereas replenishment of MAVS or OPA1 in MAVS-knockout hMSCs alleviated mitochondrial defects and premature senescence *** together,our data underscore an uncanonical role of MAVS in safeguarding mitochondrial homeostasis and antagonizing human stem cell senescence.

关键词： CRISPR/Cas9 homeostasis Mitochondrial

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A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

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Protein & Cell 2024年第2期15卷 98-120页

作者： Shanshan Yang Chengyu Liu Mengmeng Jiang Xiaoqian Liu Lingling Geng Yiyuan Zhang Shuhui Sun Kang Wang jian Yin Shuai Ma Si Wang Juan Carlos Izpisua Belmonte Weiqi Zhang Jing Qu Guang-Hui Liu Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China 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 BioinformationBeijing 100101China Xuanwu Hospital Capital Medical University Beijing 100053China 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 Aging Biomarker Consortium Beijing 100101China Altos Labs Inc.San DiegoCA 94022USA

Aging inc.eases the risk ofliver diseases and systemic susceptibility to aging-related ***,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain inc.mpletely ***,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche *** in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during *** particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular *** study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

关键词： single-nucleus RNA sequencing liver hepatocytes aging senescence SREBP2

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Gene Expression Versus Sequence for Predicting Function: Glia Maturation Factor Gamma Is Not A Glia Maturation Factor

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genomics, Proteomics & Bioinformatics 2003年第1期1卷 52-57页

作者： Michael G.Walker inc.te genomics Inc. CA 94087 USA

It is standard practice, whenever a researcher finds a new gene, to search databases for genes that have a similar sequence. It is not standard practice, whenever a researcher finds a new gene, to search for genes that have similar expression (co-expression). Failure to perform co-expression searches has lead to inc.rrect conclusions about the likely function of new genes, and has lead to wasted laboratory attempts to confirm functions inc.rrectly predicted. We present here the example of Glia Maturation Factor gamma (GMF-gamma). Despite its name, it has not been shown to participate in glia maturation. It is a gene of unknown function that is similar in sequence to GMF-beta. The sequence homology and chromosomal location led to an unsuccessful search for GMF-gamma mutations in glioma. We examined GMF-gamma expression in 1432 human cDNA libraries. Highest expression occurs in phagocytic, antigen-presenting and other hematopoietic cells. We found GMF-gamma mRNA in almost every tissue examined, with expression in nervous tissue no higher than in any other tissue. Our evidence indicates that GMF-gamma participates in phagocytosis in antigen presenting cells. Searches for genes with similar sequences should be supplemented with searches for genes with similar expression to avoid inc.rrect predictions.

关键词： gene function prediction expression analysis sequence analysis GMF-gamma

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Cost-effective low-coverage whole-genome sequencing assay for the risk stratification of gastric cancer

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World Journal of Gastrointestinal Oncology 2022年第3期14卷 690-702页

作者： Li-Ping Ye Xin-Li Mao Xian-Bin Zhou Yi Wang Shi-Wen Xu Sai-Qin He Zi-Liang Qian Xiao-Gang Zhang Li-Juan Zhai Jin-Bang Peng Bin-Bin Gu Xiu-Xiu Jin Ya-Qi Song Shao-Wei Li Key Laboratory of Minimally Invasive Techniques&Rapid Rehabilitation of Digestive System Tumor of Zhejiang Provinc. Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical UniversityLinhai 317000Zhejiang ProvinceChina Department of Gastroenterology Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical UniversityLinhai 317000Zhejiang ProvinceChina Institute of Digestive Disease Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical UniversityLinhai 317000Zhejiang ProvinceChina Taizhou Hospital of Zhejiang Provinc. Wenzhou Medical UniversityLinhai 317000Zhejiang ProvinceChina Suzhou Hongyuan Biotech inc. Suzhou 215000Zhejiang ProvinceChina prophet genomics inc. CaliforniaCA 95101United States Catcher Bio inc. Hangzhou 310000Zhejiang ProvinceChina Department of Medicine Catcher Bio Inc.Hangzhou 310000Zhejiang ProvinceChina Taizhou Hospital of Zhejiang Provinc. Zhejiang University School of MedicineLinhai 317000Zhejiang ProvinceChina

BACKGROUND Gastric cancer(GC), a multifactorial disease, is caused by pathogens, such as Helicobacter pylori(H. pylori) and Epstein-Barr virus(EBV), and genetic *** To investigate microbiomes and host genome instability by cost-effective,low-coverage wholegenome sequencing,as biomarkers for GC *** Samples from 40 GC patients were collected from Taizhou Hospital,Zhejiang Provinc.,affiliated with Wenzhou Medical *** from the samples was subjected to low-coverage wholegenome sequencing with a median genome coverage of 1.86×(range:1.03×to 3.17×) by Illumina×10,followed by copy number analyses using a customized bioinformatics workflow ultrasensitive chromosomal aneuploidy *** Of the 40 GC samples,20 (50%) were found to be enriched with *** DNA was detected in 5 GC patients (12.5%).*** DNA was found in 15 (37.5%) *** other 20(50%) patients were found to have relatively higher genomic *** number amplifications of the oncogenes,ERBB2 and KRAS,were found in 9 (22.5%) and 7 (17.5%) of the GC samples,*** enrichment was found to be associated with tumors in the gastric cardia and *** enrichment was found to be associated with tumors in the pylorus and *** with elevated genomic instability showed no localization and could be observed in any ***,***-enriched GC was found to be associated with the Borrmann type Ⅱ/Ⅲ and gastritis ***-enriched GC was not associated with *** statistically significant correlation was observed between genomic instability and ***,these three different molecular subtypes showed distinc. survival outcomes (P=0.019).EBV-positive tumors had the best prognosis,whereas patients with high genomic instability (CIN+) showed the worst *** with *** infection showed intermediate prognosis compared with the other two *** Thus,using low-coverage whole-ge

关键词： Gastric cancer Whole-genome sequencing Helicobacter pylori infections Epstein-Barr virus infections Genetic components Precision medicine

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RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

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Bone Research 2024年第1期12卷 165-179页

作者： Luis F.de Castro Jarred M.Whitlock Zachary Michel Kristen Pan Jocelyn Taylor Vivian Szymczuk Brendan Boyce Daniel Martin Vardit Kram Rebeca Galisteo Kamran Melikov Leonid V.Chernomordik Michael T.Collins Alison M.Boyce Skeletal Disorders and Mineral Homeostasis Section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Section on Membrane Biology Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA Metabolic Bone Disorders Unit National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Department of Plastic and Reconstructive Surgery The Johns Hopkins Medical InstitutionsBaltimoreMDUSA Department of Pathology and Laboratory Medicine University of Rochester Medical CenterRochesterNYUSA NIDCR genomics and Computational Biology Core National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA

Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established *** evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment *** this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical *** analysis of human and mouse tissue demonstrated inc.eased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL *** sequencing of human and mouse tissue supported these *** interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on *** results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and inc.easing osteogenic maturation,leading to inc.eased bone formation within *** findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

关键词： dysplasia treatment finding

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Are Gene Expression Microarray Analyses Reliable? A Review of Studies of Retinoic Acid Responsive Genes

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genomics, Proteomics & Bioinformatics 2003年第1期1卷 9-14页

作者： Peter J.van der Spek Andreas Kremer Lynn Murry Michael G.Walker Janssen Pharmaceutica Beerse BelgiumJanssen Pharmaceutica Beerse BelgiumIncyte Genomics Inc. CA 94087 USAIncyte Genomics Inc. CA 94087 USA

Microarray analyses of gene expression are widely used, but reports of the same analyses by different groups give widely divergent results, and raise questions regarding reproducibility and reliability. We take as an example recent published reports on microarray experiments that were designed to identify retinoic acid responsive genes. These reports show substantial differences in their results. In this article, we review the methodology, results, and potential causes of differences in these applications of microarrays. Finally, we suggest practices to improve the reliability and reproducibility of microarray experiments.

关键词： microarrays retinoic acid response gene reliability case studies

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Characterization of Adapter Protein NRBP as a Negative Regulator of T Cell Activation

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Journal of Shanghai Jiaotong university(Science) 2008年第5期13卷 605-610页

作者：王晖林志新吴骏 College of Life Sciences Fujian Normal University Shanghai genomics Inc. and Functional Genomics II of the Chinese National Human Genome Center Department of Life Science and Biotechnology Shanghai Jiaotong University

Adapter proteins can regulate the gene transcriptions in disparate signaling pathway by interacting with multiple signaling molecules, inc.uding T cell activation signaling. Nuclear receptor binding protein (NRBP), a novel adapter protein, represents a small family of evolutionarily conserved proteins with homologs in Caenorhabditis elegans (C. elegans), Drosophila melanogaster (D. melanogaster), mouse and human. Here, we demonstrated that overexpression of NRBP in Jurkat TAg cells specifically impairs T cell receptor (TCR) or phorbol myristate acetate (PMA) /ionomycin-mediated signaling leading to nuclear factor of activated T cells (NFAT) promoter activation. Furthermore, the N-terminal of NRBP is necessary for its regulation of NFAT activation. Finally, we showed that NRBP has minimal effect on both TCR- and PMA-induced CD69 up-regulation in Jurkat TAg cells, which suggests that NRBP may function downstream of protein kinase C (PKC) /Ras pathway.

关键词：核因子抗体T细胞基因表达免疫学细胞活化

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Integrating multi-modal information to detect spatial domains of spatial transcriptomics by graph attention network

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Journal of Genetics and genomics 2023年第9期50卷 720-733页

作者： Yuying Huo Yilang Guo Jiakang Wang Huijie Xue Yujuan Feng Weizheng Chen Xiangyu Li School of Software Engineering Beijing Jiaotong UniversityBeijing 100044China School of Software Engineering Beijing University of TechnologyBeijing 100124China Baidu inc. Beijing 100193China

Recent advances in spatially resolved transcriptomic technologies have enabled unprecedented opportunities to elucidate tissue architecture and function in *** transcriptomics can provide multimodal and complementary information simultaneously,inc.uding gene expression profiles,spatial locations,and histology ***,most existing methods have limitations in efficiently utilizing spatial information and matched high-resolution histology *** fully leverage the multi-modal information,we propose a SPAtially embedded Deep Attentional graph Clustering(SpaDAC)method to identify spatial domains while reconstructing denoised gene expression *** method can efficiently learn the low-dimensional embeddings for spatial transcriptomics data by constructing multi-view graph modules to capture both spatial location connectives and morphological *** results demonstrate that SpaDAC outperforms other algorithms on several recent spatial transcriptomics *** is a valuable tool for spatial domain detection,facilitating the comprehension of tissue architecture and cellular *** source code of SpaDAC is freely available at Github(https://***/huoyuying/***).

关键词： Spatialtranscriptomics Spatial domaindetection Multi-modal integration Graph attention network

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The phased chromosome-scale genome of yellowhorn sheds light on the mechanism of petal color change

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Horticultural Plant Journal 2023年第6期9卷 1193-1206页

作者： Quanxin Bi Mengke Wang Jiang Li Jinmin Lian Yongchao Niu Yifan Cui Xiaojuan Liu Haiyan Yu Libing Wang State Key Laboratory of Tree Genetics and Breeding Research Institute of ForestryChinese Academy of ForestryBeijing 100091China Biozeron Shenzhen Inc.ShenzhenGuangzhouGuangdong 518000China

Yellowhorn(Xanthoceras sorbifolium), especially its varieties, is the red petal yellowhorn(X. sorbifolium var. purpurea), an important tree species with great ornamental value, and its flower petals change color throughout the flowering period. In this study, we mainly focused on the mechanism of the petal color change with transcriptomics and metabolomics data. A phased chromosome-scale assembly of the red petal yellowhorn genome was generated using the PacBio high-fidelity reads, Illumina short reads, and Phase genomics Proximo Hi-C data. The final de novo assembly yielded 533.67 Mb with a contig N50 of 5.42 Mb, and 27 501 protein-coding genes were predicted. Notably, an alternate haplotig assembly was also obtained. Furthermore, a variation database for the alleles within the genome was constructed. Subsequently, the expression pattern of flower pigmentation-related genes and allelic expression imbalance events were investigated. Apart from 6 genes involved in the anthocyanin biosynthesis pathway regulated by the activation of 15 MYB-bHLH-WD40s, the inc.eased expression of senescencerelated gene 1(SRG1) and 2-oxoglutarate-dependent dioxygenase(DIOX5) might also result in decreasing content of lutein and inc.easing abundance of(E/Z)-phytoene, cyanidin-3-O-rutinoside, and cyanidin-3-O-sambubioside. These changes in genes and metabolites were most likely related to the petal color change in red petal yellowhorn. This phased chromosome-scale genome assembly provides more accurate genomic information for future molecular breeding and facilitates allele function studies of the red petal yellowhorn.

关键词： Xanthoceras sorbifolium var.purpurea Phased genome Metabolomics Transcriptomics Petal color

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lrys:De Novo Assembly and Structural Variation Detection in Complex Genomes Using Extremely Long Single-Molecule Imaging

lrys:De Novo Assembly and Structural Variation Detection in ...

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中国遗传学会第九次全国会员代表大会暨学术研讨会

作者： H VanSteenhouse A Hastie M Requa M Austin F Trintchouk M Saghbini X Yang H Cao BioNano genomics Inc.

De novo genome assemblies using only short read data are generally inc.mplete and highly fragmented due to the intractable complexity found in most *** complexity, consisting mainly of large duplications and repetitive regions,hinders sequence assembly and subsequent comparative analyses. The lrys platform from BioNano genomics overcomes the limitations of short fragment technologies to provide unprecedented insights into whole-genome biology,lrys is a single-molecule genome analysis system based on NanoChannel Array technology that linearizes extremely long DNA molecules for *** high-throughput platform automates massively parallel imaging of individual molecules of genomic DNA hundreds of kilobases in size to measure sufficient sequence uniqueness and long-range contiguity critical for unambiguous de novo assembly of complex ***-resolution genome maps assembled de novo retain the original context and architecture of the genome,making them extremely useful for sequence assembly scaffolding and structural variation detection applications. Specifically,these genome maps provide dense genome-wide anchor points for ordering and orienting sequencing contigs or scaffolds to greatly inc.ease completion and accuracy of de novo *** variants and repeats are measured directly within long "reads" for comprehensive analysis of what has been dubbed "the inaccessible genome".Following an introduction to the platform and underlying single-molecule technology,several examples of real-world application will demonstrate its use in large complex genomes.

关键词： Irys de novo assemblies structural variants

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