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Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma

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Cancer Communications 2024年第2期44卷 226-250页

作者： Weiren Liu Huqiang Wang Qianfu Zhao Chenyang Tao Weifeng Qu Yushan Hou Run Huang Zimei Sun Guiqi Zhu Xifei Jiang Yuan Fang Jun Gao Xiaoling Wu Zhixiang Yang Rongyu Ping Jiafeng Chen Rui Yang Tianhao Chu Jian Zhou Jia Fan Zheng Tang Dong Yang Yinghong Shi Department of Liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationShanghaiP.R.China Research Unit of Liver cancer Recurrence and Metastasis Chinese Academy of Medical SciencesBeijingP.R.China State Key Laboratory of Medical Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijingP.R.China

Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic *** metabolic reprogramming of tumor cells plays an essential role in the develop-ment of tumors,while the metabolic molecular classification of iCCA is largely ***,we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients,hoping to provide a novel perspective to understand and treat ***:We performed integrated multiomics analysis in 116 iCCA samples,including whole-exome sequencing,bulk RNA-sequencing and proteome *** on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models,the metabolic subtype of iCCA was *** and prognostic gene analy-ses were used to compare overall survival(OS)differences between metabolic *** proliferation analysis,5-ethynyl-2’-deoxyuridine(EdU)assay,colony formation assay,RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinaseα(DGKA)in iCCA ***:Three metabolic subtypes(S1-S3)with subtype-specific biomarkers of iCCA were *** metabolic subtypes presented with distinct prog-noses,metabolic features,immune microenvironments,and genetic *** S2 subtype with the worst survival showed the activation of some special metabolic processes,immune-suppressed microenvironment and Kirsten ratsar-coma viral oncogene homolog(KRAS)/AT-rich interactive domain 1A(ARID1A)*** the S2 subtype-specific upregulated proteins,DGKA was further identified as a potential drug target for iCCA,which promoted cell proliferation by enhancing phosphatidic acid(PA)metabolism and activating mitogen-activated protein kinase(MAPK)***:Viamultiomics analyses,we identified three metabolic subtypes of iCCA,revealing

关键词： diacylglycerol kinaseα intrahepatic cholangiocarcinoma MAPK signaling metabolic classifi-cation multiomics analysis phosphatidic acid metabolism

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TCM-HIN2Vec:A strategy for uncovering biological basis of heart qi deficiency pattern based on network embedding and transcriptomic experiment

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Journal of Traditional Chinese Medical Sciences 2024年第3期11卷 264-274页

作者： Lihong Diao Xinyi Fan Jiang Yu Kai Huang Edouard C.Nice Chao Liu Dong Li Shuzhen Guo School of Traditional Chinese Medicine Beijing University of Chinese MedicineBeijing 102488China Department of Biochemistry and Molecular Biology Monash UniversityClayton VIC 3800Australia Beijing Institute of Lifeomics Beijing 102206China State Key Laboratory of Medical Proteomics Beijing 102206China National center for Protein Sciences(Beijing) Beijing 102206China Beijing proteome Research center Beijing 102206China

Objective To elucidate the biological basis of the heart qi deficiency(HQD)pattern,an in-depth understanding of which is essential for improving clinical herbal *** We predicted and characterized HQD pattern genes using the new strategy,TCM-HIN2Vec,which involves heterogeneous network embedding and transcriptomic ***,a heterogeneous network of traditional Chinese medicine(TCM)patterns was constructed using public ***,we predicted HQD pattern genes using a heterogeneous network-embedding *** then analyzed the functional characteristics of HQD pattern genes using gene enrichment analysis and examined gene expression levels using ***,we identified TCM herbs that demonstrated enriched interactions with HQD pattern genes via herbal enrichment *** Our TCM-HIN2Vec strategy revealed that candidate genes associated with HQD pattern were significantly enriched in energy metabolism,signal transduction pathways,and immune ***,we found that these candidate genes were significantly differentially expressed in the transcriptional profile of mice model with heart failure with a qi deficiency ***,herbal enrichment analysis identified TCM herbs that demonstrated enriched interactions with the top 10 candidate genes and could potentially serve as drug candidates for treating *** Our results suggested that TCM-HIN2Vec is capable of not only accurately identifying HQD pattern genes,but also deciphering the basis of HQD *** our finding indicated that TCM-HIN2Vec may be further expanded to develop other patterns,leading to a new approach aimed at elucidating general TCM patterns and developing precision medicine.

关键词： Qi deficiency pattern Heart failure Biological basis Network embedding Transcriptome

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Integrative analysis of tumor stemness and immune microenvironment deciphers novel molecular subtypes in hepatocellular carcinoma

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Genes & Diseases 2024年第5期11卷 81-84页

作者： Zhiyi Wang Shuang Chen Dongxiao Li Hui Xu Siyuan Weng Yuyuan Zhang Yuqing Ren Chunguang Guo Xiuling Li Zaoqu Liu Xinwei Han Department of Interventional Radiology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Department of Gastroenterology Henan Provincial People’s HospitalZhengzhou University People’s HospitalZhengzhouHenan 450004China center of Reproductive Medicine The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Department of Respiratory and Critical Care Medicine The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Department of Endovascular Surgery The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China State Key Laboratory of Medical Molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical SciencesDepartment of PathophysiologyPeking Union Medical CollegeBeijing 100730China

Hepatocellular carcinoma(HCC)is a highly heterogeneous tumor,with dynamic equilibrium and complex interplay between its intricate tumor nature and ambient tumor immune microenvironment(TIME).1 Elegant research has indicated that cancer stem cells,a small subset of neoplastic cells confined within dedicated niches,display stem cell-like properties and interact with cells in TIME,thereby imparting an indelible impact on stemness regulation,tumor heterogeneity,and cancer cell plasticity.2 Previous taxonomies solely from the perspective of stemness or TIME may introduce some degree of bias in the comprehension of HCC carcinogenesis,3,4 and thus it is of paramount importance to systematically consider tumor stemness and TIME as a whole to truly portray the biological landscape of HCC.

关键词： thereby landscape stem

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CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence

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Science China(Life Sciences) 2024年第3期67卷 460-474页

作者： Daoyuan Huang Qian Zhao Kuan Yang Jinghui Lei Ying Jing Hongyu Li Chen Zhang Shuai Ma Shuhui Sun Yusheng Cai Guibin Wang Jing Qu Weiqi Zhang Si Wang Guang-Hui Liu Advanced Innovation centerfor Human Brain Protection National Clinical Research Centerfor Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational Medicinecenter International Centerfor Aging and CancerBejing Municipal GeriatricMedical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for Stem Cell and Regenerative Medicine Beijing100101China CAS Key Laboratory of Genomic and Precision Medicine Bejing Institute of Genomics and China National Center for BioinformationChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration CASBeijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Sino-Danish Cllege University of Chinese Academy of SciencesBeijing101408China National Laboratory of Biomacromolecules CAS Center for Excelence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China

Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining ***,we asked what roles Cullin proteins play in human mesenchymal stem cell(hMSC)homeostasis and *** this end,we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models:replicative senescent hMSCs,Hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome *** all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to *** investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells(hESCs).When we differentiated these into h MSCs,we found that CUL2 deletion markedly accelerates hMSC ***,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays *** work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

关键词： Cullins stem cell senescence aging proteostasis ubiquitination APPBP2 TSPYL2

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Proteomic Stratification of Prognosis and Treatment Options for Small Cell Lung Cancer

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Genomics, Proteomics & Bioinformatics 2024年第2期22卷 81-92页

作者： Zitian Huo Yaqi Duan Dongdong Zhan Xizhen Xu Nairen Zheng Jing Cai Ruifang Sun Jianping Wang Fang Cheng Zhan Gao Caixia Xu Wanlin Liu Yuting Dong Sailong Ma Qian Zhang Yiyun Zheng Liping Lou Dong Kuang Qian Chu Jun Qin Guoping Wang Yi Wang Institute of Pathology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Pathology School of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China National Health Commission Key Laboratory of Respiratory Diseases Tongji HosptialTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Beijing Pineal Diagnostics Co. Ltd.Beijing 102206China Department of Oncology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China Institution of Pathology The First Affiliated Hospital of Henan UniversityKaifeng 475001China Department of Tumor Biobank Shanxi Cancer HospitalTaiyuan 030013China Chongqing Key Laboratory of Big Data for Bio Intelligence School of BioinformationChongqing University of Posts and TelecommunicationsChongqing 400065China

Small cell lung cancer(SCLC)is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction ***,we analyzed formalin-fixed,paraffin-embedded(FFPE)samples of surgical resections by proteomic profiling,and stratified SCLC into three proteomic subtypes(S-I,S-II,and S-III)with distinct clinical outcomes and chemotherapy *** proteomic subtyping was an independent prognostic factor and performed better than current tumor–node–metastasis or Veterans Administration Lung Study Group staging *** subtyping results could be further validated using FFPE biopsy samples from an independent cohort,extending the analysis to both surgical and biopsy *** signatures of the S-II subtype in particular suggested potential benefits from *** overexpressed proteins in S-III,the worst prognostic subtype,allowed us to nominate potential therapeutic targets,indicating that patient selection may bring new hope for previously failed clinical ***,analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line ***,our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.

关键词： Small cell lung cancer Proteomics Prognosis Chemotherapy response Immunotherapy

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Amplifiable protein identification via residue-resolved barcoding and composition code counting

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National Science Review 2024年第7期11卷 205-217页

作者： Weiming Guo Yuan Liu Yu Han Huan Tang Xinyuan Fan Chu Wang Peng R.Chen Synthetic and Functional Biomolecules center Beijing National Laboratory for Molecular SciencesKey Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of EducationCollege of Chemistry and Molecular Engineering Peking University Peking-Tsinghua center for Life Sciences Academy for Advanced Interdisciplinary Studies Peking University

Ultrasensitive protein identification is of paramount importance in basic research and clinical diagnostics but remains extremely challenging. A key bottleneck in preventing single-molecule protein sequencing is that, unlike the revolutionary nucleic acid sequencing methods that rely on the polymerase chain reaction(PCR) to amplify DNA and RNA molecules, protein molecules cannot be directly amplified. Decoding the proteins via amplification of certain fingerprints rather than the intact protein sequence thus represents an appealing alternative choice to address this formidable challenge. Herein, we report a proof-of-concept method that relies on residue-resolved DNA barcoding and composition code counting for amplifiable protein fingerprinting(AmproCode). In AmproCode, selective types of residues on peptides or proteins are chemically labeled with a DNA barcode, which can be amplified and quantified via quantitative PCR. The operation generates a relative ratio as the residue-resolved ‘composition code’ for each target protein that can be utilized as the fingerprint to determine its identity from the proteome database. We developed a database searching algorithm and applied it to assess the coverage of the whole proteome and secretome via computational simulations, proving the theoretical feasibility of AmproCode. We then designed the residue-specific DNA barcoding and amplification workflow, and identified different synthetic model peptides found in the secretome at as low as the fmol/L level for demonstration. These results build the foundation for an unprecedented amplifiable protein fingerprinting method. We believe that, in the future,AmproCode could ultimately realize single-molecule amplifiable identification of trace complex samples without further purification, and it may open a new avenue in the development of next-generation protein sequencing techniques.

关键词： protein identification amplifiable fingerprinting residue-specific chemistry DNA barcoding composition code counting

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Lifeomics leads the age of grand discoveries

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Science China(Life Sciences) 2013年第3期56卷 201-212页

作者： HE FuChu State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Science(Beijing)

When our knowledge of a field accumulates to a certain level,we are bound to see the rise of one or more great *** will make a series of grand discoveries/breakthroughs and push the discipline into an 'age of grand discoveries'.Mathematics,geography,physics and chemistry have all experienced their ages of grand discoveries;and in life sciences,the age of grand discoveries has appeared countless times since the 16th *** to the ever-changing development of molecular biology over the past 50 years,contemporary life science is once again approaching its breaking point and the trigger for this is most likely to be 'lifeomics'.At the end of the 20th century,genomics wrote out the 'script of life';proteomics decoded the script;and RNAomics,glycomics and metabolomics came into *** 'omics',with their unique epistemology and methodology,quickly became the thrust of life sciences,pushing the discipline to new ***,which encompasses all omics,has taken shape and is now signalling the dawn of a new era,the age of grand discoveries.

关键词： age of grand discoveries lifeomics life sciences

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An integrated view of the correlations between genomic and phenomic variables

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Journal of Genetics and Genomics 2009年第11期36卷 645-651页

作者： Dong Yang,Ying Jiang,Fuchu He State Key Laboratory of Proteomics,Beijing proteome Research center,Beijing Institute of Radiation Medicine,Beijing 102206,China State Key Laboratory of Proteomics Beijing Proteome Research Center Beijing Institute of Radiation Medicine Beijing 102206 China

Genome sequencing opened the flood gate of ＂-omics＂ studies, among which the research about correlations between genomic and phenomic variables is an important part. With the development of functional genomics and systems biology, genome-wide investigation of the correlations between many genomic and phenomic variables became possible. In this review, five genomic variables, such as evolution rate （or ＂age＂ of the gene）, the length of intron and ORF （protein length） in one gene, the biases of amino acid composition and codon usage, along with the phenomic variables related to expression patterns （level and breadth） are focused on. In most cases, genes with higher mRNA/protein expression level tend to evolve slowly, have less intronic DNA, code for smaller proteins, and have higher biases of amino acid composition and codon usage. In addition, broadly expressed proteins evolve more slowly and are shorter than tissue-specific proteins. Studies in this field are helpful for deeper understanding the signatures of selection mediated by the features of gene expression and are of great significance to enrich the evolution theory.

关键词： genomic variable phenomic variable expression pattern evolution selection

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Nanoscale Reorganization of Glutamate Receptors Underlies Synaptic Plasticity and Pathology

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Neuroscience Bulletin 2024年第6期40卷 840-844页

作者： Jia-Hui Chen Ai-Hui Tang Hefei National Laboratory for Physical Sciences at the Microscale CAS Key Laboratory of Brain Function and DiseaseNeurodegenerative Disorder Research Center and Biomedical Sciences and Health Laboratory of Anhui ProvinceUniversity of Science and Technology of ChinaHefei230027China Institute of Artificial Intelligence Hefei Comprehensive National Science CenterHefei230088China

Excitatory synapses serve as the primary sites for information transmission between neurons in the *** work over the past decades has identified and revealed multiple compositions and functions of the synaptic proteome in the postsynaptic density(PSD),including receptors,scaffold proteins,and signaling molecules,which work together to ensure stable and effective synaptic transmission.

关键词： Receptor scale Glutamate

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An ultra-fast and highly efficient multiple proteases digestion strategy using graphene-oxide-based immobilized protease reagents

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Science China Chemistry 2014年第5期57卷 695-702页

作者： BAI HaiHong PAN YiTing REN XiaoJun HAO FeiRan DENG ShanShan FAN Chao YAN Hui SHEN BingQuan MA Lin TIAN Fang PENG Bo DENG YuLin QIN WeiJie QIAN XiaoHong School of Life Science and Technology Beijing Institute of Technology National center for Protein Sciences Beijing State Key Laboratory of Proteomics Beijing Proteome Research CenterBeijing Institute of Radiation Medicine

Highly efficient and rapid proteolytic digestion of proteins into peptides is a crucial step in shotgun-based proteome-analysis strategy. Tandem digestion by two or more proteases is demonstrated to be helpful for increasing digestion efficiency and de- creasing missed cleavages, which results in more peptides that are compatible with mass-spectrometry analysis. Compared to conventional solution digestion, immobilized protease digestion has the obvious advantages of short digestion time, no self-proteolysis, and reusability. We proposed a multiple-immobilized proteases-digestion strategy that combines the ad- vantages of the two digestion strategies mentioned above. Graphene-oxide （GO）-based immobilized trypsin and endoprotein- ase Glu-C were prepared by covalently attaching them onto the GO surface. The prepared GO-trypsin and GO-Glu-C were successfully applied in standard protein digestion and multiple immobilized proteases digestion of total proteins of Thermoan- aerobacter tengcongensis. Compared to 12-hour solution digestion using trypsin or Glu-C, 14% and 7% improvement were obtained, respectively, in the sequence coverage of BSA by one-minute digestion using GO-trypsin and GO-GIu-C. Multiple immobilized-proteases digestion of the total proteins of Thermoanaerobacter tengcongensis showed 24.3% and 48.7% en- hancement in the numbers of identified proteins than was obtained using GO-trypsin or GO-Glu-C alone. The ultra-fast and highly efficient digestion can be contributed to the high loading capacity of protease on GO, which leads to fewer missed cleavages and more complete digestion. As a result, improved protein identification and sequence coverage can be expected.

关键词： graphene oxide Trypsin GIu-C immobilized protease multiple proteases digestion

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