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Low-density lipoprotein receptor-related protein 1 is a CROPs-associated receptor for Clostridioides infection toxin B

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Science China(Life Sciences) 2022年第1期65卷 107-118页

作者： Shengjie Guo Yiou Chen Jingze Liu Xinyi Zhang Zhiheng Liu Zhuo Zhou Wensheng Wei Biomedical Pioneering Innovation Center Beijing Advanced Innovation Center for GenomicsPeking-Tsinghua Center for Life SciencesPeking University Genome Editing Research CenterState Key Laboratory of Protein and Plant Gene ResearchSchool of Life SciencesPeking UniversityBeijing 100871China

As the leading cause of worldwide hospital-acquired infection,Clostridioides difficile(C.difficile)infection has caused heavy economic and hospitalized burden,while its pathogenesis is not fully understood.Toxin B(Tcd B)is one of the major virulent factors of C.difficile.Recently,CSPG4 and FZD2 were reported to be the receptors that mediate Tcd B cellular entry.However,genetic ablation of genes encoding these receptors failed to completely block Tcd B entry,implicating the existence of alternative receptor(s)for this toxin.Here,by employing the CRISPR-Cas9 screen in CSPG4-deficient He La cells,we identified LDL receptor-related protein-1(LRP1)as a novel receptor for Tcd B.Knockout of LRP1 in both CSPG4-deficient He La cells and colonic epithelium Caco2 cells conferred cells with increased Tcd B resistance,while LRP1 overexpression sensitized cells to Tcd B at a low concentration.Co-immunoprecipitation assay showed that LRP1 interacts with full-length Tcd B.Moreover,CROPs domain,which is dispensable for Tcd B’s interaction with CSPG4 and FZD2,is sufficient for binding to LRP1.As such,our study provided evidence for a novel mechanism of Tcd B entry and suggested potential therapeutic targets for treating C.difficile infection.

关键词： Clostridioides difficile low-density lipoprotein receptor-related protein 1 Tcd B toxin receptor CRISPR screening

Crystal structures of N-terminal WRKY transcription factors and DNA complexes

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Protein & Cell 2020年第3期11卷 208-213页

作者： Yong-ping Xu Hua Xu Bo Wang Xiao-Dong Su State Key Laboratory of Protein and Plant Gene Research and Biomedical Pioneering Innovation Center(BIOPIC)Peking UniversityBeijing 100871China

Dear Editor,Plant-specific WRKY transcription factors(TFs)are among the largest families of TFs in higher plants;they are also found in the unicellular eukaryote Giardia lamblia and the slime mold Dictyostelium discoideum(Ulker and Somssich,2004),but not in animals.WRKY TFs participate in diverse developmental and physiological processes in plants,such as disease resistance,abiotic stress responses,senescence,seed and trichome development,as well as additional developmental and hormone-controlled processes(Agarwal et al.,2011).

关键词： complexes families Crystal

Cancer biology deciphered by single-cell transcriptomic sequencing

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Protein & Cell 2022年第3期13卷 167-179页

作者： Yanmeng Li Jianshi Jin Fan Bai Biomedical Pioneering Innovation Center(BIOPIC) School of Life SciencesPeking UniversityBeijing 100871China RIKEN center for Biosystems Dynamics Research(BDR) 6-2-3FuruedaiSuitaOsakaJapan Beijing Advanced innovation center for Genomics(ICG) Peking UniversityBeijing 100871China

Tumors are complex ecosystems in which heterogeneous cancer cells interact with their microenvironment composed of diverse immune,endothelial,and stromal cells.Cancer biology had been studied using bulk genomic and gene expression profiling,which however mask the cellular diversity and average the variability among individual molecular programs.Recent advances in single-cell transcriptomic sequencing have enabled a detailed dissection of tumor ecosystems and promoted our understanding of tumorigenesis at single-cell resolution.In the present review,we discuss the main topics of recent cancer studies that have implemented singlecell RNA sequencing(scRNA-seq).To study cancer cells,scRNA-seq has provided novel insights into the cancer stem-cell model,treatment resistance,and cancer metastasis.To study the tumor microenvironment,scRNA-seq has portrayed the diverse cell types and complex cellular states of both immune and non-immune cells interacting with cancer cells,with the promise to discover novel targets for future immunotherapy.

关键词： single-cell transcriptomic sequencing tumor microenvironment cancer

Recent advances in single-cell sequencing technologies

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Precision Clinical Medicine 2022年第1期5卷 13-22页

作者： Lu Wen Fuchou Tang Beijing Advanced innovation center for Genomics(ICG) Biomedical Pioneering Innovation Center(BIOPIC)School of Life SciencesPeking UniversityBeijing 100871China

Single-cell omics sequencingwas first achieved for the transcriptome in 2009,whichwas followed by fast development of technologies for profiling the genome,DNA methylome,3D genome architecture,chromatin accessibility,histone modifications,etc.,in an individual cell.In this review we mainly focus on the recent progress in four topics in the single-cell omics field:single-cell epigenome sequencing,single-cell genome sequencing for lineage tracing,spatially resolved single-cell transcriptomics and third-generation sequencing platform-based single-cell omics sequencing.We also discuss the potential applications and future directions of these single-cell omics sequencing technologies for different biomedical systems,especially for the human stem cell field.

关键词： single-cell omics genome sequencing epigenome sequencing lineage tracing third-generation sequencing human stem cell

Interrogating the noncoding genome in a high-throughput fashion

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National Science Review 2019年第3期6卷 397-399页

作者： Zhuo Zhou Wensheng Wei Biomedical Pioneering Innovation Center (BIOPIC) Beijing Advanced Innovation Center for GenomicsPeking-Tsinghua Center for Life Sciences Peking University Genome Editing Research Center State Key Laboratory of Protein and Plant Gene Research School of Life Sciences Peking University

The vast majority of the mammalian genome consists of DNAs that do not encode protein sequences. For decades, the functional potentials of these noncoding DNAs have remained poorly understood. Large-scale studies, such as the Encyclopedia of DNA Elements project and genome-wide association studies, have suggested that the noncoding genome functions in a wide variety of biological and physiological process [1]. However,

关键词： Interrogating the noncoding genome in a high-throughput fashion CRISPRi

Decoding Human Biology and Disease Using Single-cell Omics Technologies

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Genomics, Proteomics & Bioinformatics 2023年第5期21卷 926-949页

作者： Qiang Shi Xueyan Chen Zemin Zhang Biomedical Pioneering Innovation Center School of Life SciencesPeking UniversityBeijing 100871China Peking-Tsinghua center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100871China Changping Laboratory Beijing 102206China

Over the past decade,advances in single-cell omics(SCO)technologies have enabled the investigation of cellular heterogeneity at an unprecedented resolution and scale,opening a new avenue for understanding human biology and disease.In this review,we summarize the developments of sequencing-based SCO technologies and computational methods,and focus on considerable insights acquired from SCO sequencing studies to understand normal and diseased properties,with a particular emphasis on cancer research.We also discuss the technological improvements of SCO and its possible contribution to fundamental research of the human,as well as its great potential in clinical diagnoses and personalized therapies of human disease.

关键词： Single-cell omics Computational method Cellular heterogeneity Disease Cancer research

Single-cell transcriptomics of immune cells in lymph nodes reveals their composition and alterations in functional dynamics during the early stages of bubonic plague

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Science China(Life Sciences) 2023年第1期66卷 110-126页

作者： Yifan Zhao Tong Wang Ziyang Liu Yuehua Ke Ruoyan Li Hongyan Chen Yang You Gengshan Wu Shiyang Cao Zongmin Du Fan Bai Ruifu Yang Biomedical Pioneering Innovation Center(BIOPIC) School of Life SciencesPeking UniversityBeijing 100871China State Key Laboratory of Pathogen and Biosecurity Beijing Institute of Microbiology and EpidemiologyBeijing 100071China center for Disease Control and Prevention of Chinese People’s Liberation Army Beijing 100071China

Bubonic plague caused by Yersinia pestis is highly infectious and often fatal.Characterization of the host immune response and its subsequent suppression by Y.pestis is critical to understanding the pathogenesis of Y.pestis.Here,we utilized single-cell RNA sequencing to systematically profile the transcriptomes of immune cells in draining lymph nodes(d LNs)during the early stage of Y.pestis infection.Dendritic cells responded to Y.pestis within 2 h post-infection(hpi),followed by the activation of macrophages/monocytes(Mφs/Mons)and recruitment of polymorphonuclear neutrophils(PMNs)to d LNs at 24 hpi.Analysis of cell-to-cell communication suggests that PMNs may be recruited to lymph nodes following the secretion of CCL9 by Mφs/Mons stimulated through CCR1-CCL9 interaction.Significant functional suppression of all the three innate immune cell types occurred during the early stage of infection.In summary,we present a dynamic immune landscape,at single-cell resolution,of murine d LNs involved in the response to Y.pestis infection,which may facilitate the understanding of the plague pathogenesis of during the early stage of infection.

关键词： bubonic plague single-cell RNA sequencing Yersinia pestis

Screening for inhibitors against SARS-CoV-2 and its variants

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Biosafety and Health 2022年第3期4卷 186-192页

作者： Weijing Yuan Xiaojing Dong Lan Chen Xiaobo Lei Zhuo Zhou Li Guo Jianwei Wang Institute of Pathogenic Biology Peking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100730China School of Life Science Peking UniversityBeijing 100871China Biomedical Pioneering Innovation Center Peking UniversityBeijing 100871China

Severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)continues to evolve,generating new variants that pose a threat to global health;therefore,it is imperative to obtain safe and broad‐spectrum antivirals against SARS‐CoV‐2 and its variants.To this end,we screened compounds for their ability to inhibit viral entry,which is a critical step in virus infection.Twenty compounds that have been previously reported to inhibit SARS‐CoV‐2 replication were tested by using pseudoviruses containing the spike protein from the original strain(SARS‐CoV‐2‐WH01).The cytotoxicity of these compounds was determined.Furthermore,we identified six compounds with strong antagonistic activity against the WH01 pseudovirus,and low cytotoxicity was identified.These compounds were then evaluated for their efficacy against pseudoviruses expressing the spike protein from B.1.617.2(Delta)and B.1.1.529(Omicron),the two most prevalent circulating strains.These assays demonstrated that two phenothiazine compounds,trifluoperazine 2HCl and thioridazine HCl,inhibit the infection of Delta and Omicron pseudoviruses.Finally,we discovered that these two compounds were highly effective against authentic SARS‐CoV‐2 viruses,including the WH01,Delta,and Omicron strains.Our study identified potential broad‐spectrum SARS‐CoV‐2 inhibitors and provided insights into the development of novel therapeutics.

关键词： SARS‐CoV‐2 Delta variant Omicron variant Trifluoperazine 2HCl Thioridazine HCl Antiviral therapy

Rationally designed synthetic peptide as versatile calibrant to improve the accuracy of protein sequence analysis using MALDI mass spectrometry

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Chinese Chemical Letters 2024年第3期35卷 214-220页

作者： Lingpeng Zhan Yanyi Huang Guanbo Wang Institute for Cell Analysis Shenzhen Bay LaboratoryShenzhen 518132China Biomedical Pioneering Innovation Center Peking UniversityBeijing 100871China

Matrix-assisted laser desorption/ionization(MALDI)mass spectrometry(MS)plays an indispensable role in analyzing protein covalent structures.The reliable identification of amino acid residues and modifications relies on the mass accuracy,which is highly dependent on calibration.However,the accuracy provided by the currently available calibrants still needs further improvement in terms of compatibility with multiple tandem MS modes or ion polarity modes,calibratable range,and minimizing suppression of and interference with analyte signals.Here aiming at developing a versatile calibrant to solve these problem,we designed a synthetic peptide format of calibrant R_x(GDP_n)_m(referred to as“Gly-Asp-Pro,GDP”)according to the chemical natures of amino acids and polypeptide fragmentation rules in tandem MS.With four types of amino acid residues selected and arranged through rational designs,a GDP peptide produces highly regulated fragments that give rise to evenly spaced signals in each tandem MS mode and is compatible with both positive and negative ion modes.In internal calibration,its regulated fragmentation pattern minimizes interference with analyte signals,and using a single peptide as the input minimizes suppression of the analyte signals.As demonstrated by analyses of proteins including monoclonal antibody and Aβ-42,these features allowed significant increase of the mass accuracy and precision,which improved sequence coverage and sequence resolution in sequence analyses(including de novo sequencing).This rational design strategy may also inspire further development of synthetic calibrants that benefit structural analysis of biomolecules.

关键词： Biomolecule design Synthetic peptide Protein sequencing Covalent structure De novo sequencing Mass spectrometry Gas-phase fragmentation