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RePhine: An Integrative Method for Identification of Drug Response-related Transcriptional Regulators

Genomics, Proteomics & bioinformatics 2021年第4期19卷 534-548页

作者： Xujun Wang Zhengtao Zhang Wenyi Qin Shiyi Liu Cong Liu Georgi ZGenchev Lijian Hui Hongyu Zhao Hui Lu SJTU-Yale Joint center for Biostatistics and Data Science Department of Bioinformatics and BiostatisticsSchool of Life Science and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyShanghai 200031China Department of Bioengineering University of Illinois at ChicagoIL 60607USA Department of Genetics School of MedicineYale UniversityNew HavenCT 06511USA Department of Medical Informatics Columbia UniversityNew YorkNY 10032USA Bulgarian Institute for Genomics and Precision Medicine Sofia 1000Bulgaria Department of Biostatistics Yale School of Public Health.New HavenCT 06511USA Institute of Science and Technology for Brain-Inspired Intelligence Fudan UniversityShanghai 200433China center for Biomedical informatics Shanghai Children’s HospitalShanghai 200040China

Transcriptional regulators(TRs)participate in essential processes in cancer pathogenesis and are critical therapeutic *** of drug response-related TRs from cell line-based compound screening data is often challenging due to low m RNA abundance of TRs,protein modifications,and other confounders(CFs).In this study,we developed a regression-based pharmacogenomic and Ch IP-seq data integration method(Re Phine)to infer the impact of TRs on drug response through integrative analyses of pharmacogenomic and Ch IP-seq *** Phine was evaluated in simulation and pharmacogenomic data and was applied to pan-cancer datasets with the goal of biological *** simulation data with added noises or CFs and in pharmacogenomic data,Re Phine demonstrated an improved performance in comparison with three commonly used methods(including Pearson correlation analysis,logistic regression model,and gene set enrichment analysis).Utilizing Re Phine and Cancer Cell Line Encyclopedia data,we observed that Re Phinederived TR signatures could effectively cluster drugs with different mechanisms of *** Phine predicted that loss-offunction of EZH2/PRC2 reduces cancer cell sensitivity toward the BRAF inhibitor *** validation confirmed that pharmacological EZH2 inhibition increases the resistance of cancer cells to PLX4720 *** results support that Re Phine is a useful tool for inferring drug response-related TRs and for potential therapeutic *** source code for Re Phine is freely available at https://***/coexps/Re Phine.

关键词： Pharmacogenomics ChIP-seq Transcriptional regulator BRAF inhibitor resistance Drug resistance

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Analysis and application of large-scale protein-protein interaction data sets

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Chinese Science Bulletin 2005年第20期50卷 2267-2272页

作者： SUN Jingchun XU Jinlin LI Yixue SHI Tieliu School of Life Sciences & Technology Shanghai Jiaotong University Shanghai 200240 China Bioinformation center Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 200031 China

Protein-protein interactions play key roles in cells. Lots of experimental approaches and in silico methods have been developed to identify and predict large-scale pro- tein-protein interactions. However, compared with the tradi- tionally experimental results, the high-throughput pro- tein-protein interaction data often contain the false positives in high probability. In order to fully utilize the large-scale data, it is necessary to develop bioinformatic methods for systematically evaluating those data in order to further im- prove the data reliability and mine biological information. This review summarizes the methodologies of analysis and application of high-throughput protein-protein interaction data, including the evaluation methods, the relationship be- tween protein-protein interaction data and other protein biological information, and their applications in biological study. In addition, this paper also suggests some interesting topics on mining high-throughput protein-protein interaction data.

关键词：蛋白质交互作用生物学功能预测生物途径

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Bioinformatic analysis of human nuclear receptor nr5a2(hb1f) genomic sequence

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Chinese Science Bulletin 2002年第7期47卷 568-572,617页

作者： Zhang Chengkang Lin Wei Cai Yanning Dong Hui Li Mei Fu Gang Xie Youhua Huang M.Guyang Wang Yuan Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological SciencesChinese Academy of Sciences200031ShanghaiChina Chinese Human Genome center at shanghai 201203ShanghaiChina

We have cloned the cDNA of human nuclear receptor nr5a2(hb1f) gene and obtained its whole genomic sequence previously. In this work we carried out in-depth bioinformatic analysis on the genomic sequence of nr5a2(hb1f) gene. Sequence comparison and prediction algorithms implicated that there might be additional coding regions in the 210 kb genomic sequence besides known exons, especially in the two largest introns. Comparison of the structures of nr5a loci in different species revealed distinguishable conservation and apparent gene duplication during evolution. The remarkable conservation among promoters of zebrafish, mouse and human nr5a2 genes suggested that they would be regulated by the same transcription factors.

关键词： nuclear receptor nr5a2(hb1f) gene structure bioinfor-matics comparative genomics.

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The Reference Genome Sequence of Scutellaria baicalensis Provides Insights into the Evolution of Wogonin Biosynthesis

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Molecular Plant 2019年第7期12卷 935-950页

作者： Qing Zhao Jun Yang Meng-Ying Cui Jie Liu Yumin Fang Mengxiao Yan Wenqing Qiu Huiwen Shang Zhicheng Xu Reheman Yidiresi Jing-Ke Weng Tomas Pluskal Marielle Vigouroux Burkhard Steuernagel Yukun Wei Lei Yang Yonghong Hu Xiao-Ya Chen Cathie Martin shanghai Key Laboratory of Plant Functional Genomics and Resources Shanghai Chenshan Botanical Garden Shanghai Chenshan Plant Science Research Center Chinese Academy of Sciences Shanghai China State Key Laboratory of Plant Molecular Genetics CAS Center for Excellence in Molecular Plant Sciences Shanghai Institute of Plant Physiology and Ecology Chinese Academy of Sciences Shanghai China Key Laboratory of Metabolism and Molecular Medicine Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Fudan University Shanghai China Novogene bioinformatics Institute Beijing China Whitehead Institute for Biomedical Research 455 Main Street Cambridge MA 02142 USA Department of Biology Massachusetts Institute of Technology Cambridge MA 02139 USA John Innes Centre Norwich NR4 7UH UK

Scutellaria baicalensis Georgi is important in Chinese traditional medicine where preparations of dried roots,"Huang Qin," are used for liver and lung complaints and as complementary cancer treatments. We report a high-quality reference genome sequence for S. baicalensis where 93% of the 408.14-Mb genome has been assembled into nine pseudochromosomes with a super-N50 of 33.2 Mb. Comparison of this sequence with those of closely related species in the order Lamiales, sesamum indicum and Salvia splendens,revealed that a specialized metabolic pathway for the synthesis of 4'-deoxyflavone bioactives evolved in the genus Scu-tellaria. We found that the gene encoding a specific cinnamate coenzyme A ligase likely obtained its newfunc- tion following recent mutations, and that four genes encoding enzymes in the 4'-deoxyflavone pathway are present as tandem repeats in the genome of S. baicalensis. Further analyses revealed that gene duplications, segmental duplication, gene amplification, and point mutations coupled to gene neo- and subfunctionaliza-tions were involved in the evolution of 4'-deoxyflavone synthesis in the genus Scutellaria. Our study not only provides significant insight into the evolution of specific flavone biosynthetic pathways in the mint family, Lamiaceae, but also will facilitate the development of tools for enhancing bioactive productivity by metabolic engineering in microbes or by molecular breeding in plants. The reference genome of S. baicalensis is also useful for improving the genome assemblies for other members of the mint family and offers an important foundation for decoding the synthetic pathways of bioactive compounds in medicinal plants.

关键词： genome skullcap 4’-deoxyflavone traditional Chinese medicine Huang Qin:evolution specialized metabolism

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Enhancer-derived RNA:A Primer

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Genomics, Proteomics & bioinformatics 2017年第3期15卷 196-200页

作者： Feng Liu National Research center for Translational Medicine Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China

Enhancer-derived RNAs （eRNAs） are a group of RNAs transcribed by RNA polymerase II from the domain of transcription enhancers, a major type of cis-regulatory elements in the genome. The correlation between eRNA production and enhancer activity has stimulated studies on the potential role of eRNAs in transcriptional regulation. Additionally, eRNA has also served as a marker for global identification of enhancers. Here I review the brief history and fascinating properties of eRNAs.

关键词： eRNA Enhancer Next-generation sequencing Non-coding RNA Gene regulation

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Profiling of immune features to predict immunotherapy efficacy

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The Innovation 2022年第1期3卷 71-82页

作者： Youqiong Ye Yongchang Zhang Nong Yang Qian Gao Xinyu Ding Xinwei Kuang Rujuan Bao Zhao Zhang Chaoyang Sun Bingying Zhou Li Wang Qingsong Hu Chunru Lin Jianjun Gao Yanyan Lou Steven HLin Lixia Diao Hong Liu Xiang Chen Gordon B.Mills Leng Han shanghai Institute of Immunology Department of Immunology and MicrobiologyShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Biochemistry and Molecular Biology The University of Texas Health Science Center at Houston McGovern Medical SchoolHoustonTX 77030USA Department of Medical Oncology Lung Cancer and Gastrointestinal UnitHunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaHunan 410008China Department of Dermatology Xiangya HospitalCentral South UniversityChangshaHunan 410008China Department of Obstetrics and Gynecology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China State Key Laboratory of Cardiovascular Disease Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Genitourinary Medical Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Division of Hematology and Oncology Mayo ClinicJacksonvilleFL 32224USA Department of Radiation Oncology Division of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of bioinformatics and Computational Biology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Knight Cancer Institute Oregon Health and Science UniversityPortlandOR 97239USA center for Epigenetics and Disease Prevention Institute of Biosciences and TechnologyTexas A&M UniversityHoustonTX 77030USA Department of Translational Medical Sciences College of MedicineTexas A&M UniversityHoustonTX 77030 USA

Immune checkpoint blockade(ICB)therapies exhibit substantial clinical benefit in different cancers,but relatively low response rates in the majority of patients highlight the need to understand mutual relationships among immune ***,we reveal overall positive correlations among immune checkpoints and immune cell ***,patients benefiting from ICB exhibited increases for both immune stimulatory and inhibitory features after initiation of therapy,suggesting that the activation of the immune microenvironment might serve as the biomarker to predict immune *** proof-of-concept,we demonstrated that the immune activation score(ISD)based on dynamic alteration of interleukins in patient plasma as early as two cycles(4-6 weeks)after starting immunotherapy can accurately predict immunotherapy *** results reveal a systematic landscape of associations among immune features and provide a noninvasive,cost-effective,and time-efficient approach based on dynamic profiling of pre-and on-treatment plasma to predict immunotherapy efficacy.

关键词： immunotherapy features mutual

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The cancer-testis gene,MEIOB,sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency

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Cancer Biology & Medicine 2021年第1期18卷 74-87页

作者： Yayun Gu Cheng Wang Rongxuan Zhu Jianshui Yang Wenwen Yuan Yanhui Zhu Yan Zhou Na Qin Hongbing Shen Hongxia Ma Hongxia Wang Xiaoan Liu Zhibin Hu State Key Laboratory of Reproductive Medicine Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjing 211166China Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentJiangsu Collaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjing 211116China Department of bioinformatics School of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing 211166China Department of Oncology Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200080China Department of Breast Surgery The First Affiliated Hospital with Nanjing Medical UniversityNanjing 210029China

Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)*** this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of *** regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human *** effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in ***-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 ***:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially *** activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC *** analysis showed that MEIOB participated in DSB repair in ***,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with ***,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX ***:MEIOB played an oncogenic role in TNBC through its involvement in *** addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.

关键词： Cancer-testis gene MEIOB triple-negative breast cancer PARP1 inhibitor cell proliferation

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A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis

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Acta Pharmaceutica Sinica B 2021年第3期11卷 708-726页

作者： Tailin He Jialin Shang Chenglong Gao Xin Guan Yingyi Chen Liwen Zhu Luyong Zhang Cunjin Zhang Jian Zhang Tao Pang State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug ScreeningJiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesChina Pharmaceutical UniversityNanjing 210009China Medicinal bioinformatics center Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of Neurology of Drum Tower Hospital Medical School and the State Key Laboratory of Pharmaceutical BiotechnologyNanjing UniversityNanjing 210008China

Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke,but how to control the overactive neuroinflammation is still a long-standing ***,we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia,which were abolished by silencing ***-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811stimulation and is required for the anti-inflammatory effects of *** found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate ***,our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS,but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional ***,MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients,underlying an interesting translational *** together,MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation.

关键词： SIRT6 activator Neuroinflammation Ischemic stroke Deacetylation Microglia Macrophage FOXC1 EZH2

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Hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p inhibitors can reduce the cytotoxicity of Ebola virus glycoprotein in vitro

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Science China(Life Sciences) 2014年第10期57卷 959-972页

作者： SHENG MiaoMiao ZHONG Ying CHEN Yang DU JianChao JU XiangWu ZHAO Chen ZHANG GuiGen ZHANG LiFang LIU KangTai YANG Ning XIE Peng LI DangSheng ZHANG Michael Q. JIANG ChengYu State Key Laboratory of Medical Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences Department of Biochemistry and Molecular Biology Peking Union Medical College Tsinghua University MOE Key Laboratory of bioinformatics and bioinformatics Division Center for Synthetic and System Biology TNLIST/Department of Automation Tsinghua University shanghai Institutes for Biological Sciences Chinese Academy of Sciences Department of Molecular and Cell Biology Center for Systems Biology The University of Texas State Key Laboratory of Biotherapy/Collaborative Innovation center for Biotherapy West China Hospital Sichuan University

Ebola virus(EBOV)causes a highly lethal hemorrhagic fever syndrome in humans and has been associated with mortality rates of up to 91%in Zaire,the most lethal *** the viral envelope glycoprotein(GP)mediates widespread inflammation and cellular damage,these changes have mainly focused on alterations at the protein level,the role of microRNAs(miRNAs)in the molecular pathogenesis underlying this lethal disease is not fully ***,we report that the miRNAs hsa-miR-1246,hsa-miR-320a and hsa-miR-196b-5p were induced in human umbilical vein endothelial cells(HUVECs)following expression of EBOV *** the proteins encoded by predicted targets of these miRNAs,the adhesion-related molecules tissue factor pathway inhibitor(TFPI),dystroglycan1(DAG1)and the caspase 8 and FADD-like apoptosis regulator(CFLAR)were significantly downregulated in EBOV GP-expressing ***,inhibition of hsa-miR-1246,hsa-miR-320a and hsa-miR-196b-5p,or overexpression of TFPI,DAG1 and CFLAR rescued the cell viability that was induced by EBOV *** results provide a novel molecular basis for EBOV pathogenesis and may contribute to the development of strategies to protect against future EBOV pandemics.

关键词：病毒糖蛋白体外细胞毒性抑制剂人脐静脉内皮细胞蛋白质水平微RNA 组织因子途径分子基础

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Multiple analyses indicate the specific association of NR1I3,C6 and TNN with low hip BMD risk

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Journal of Genetics and Genomics 2017年第6期44卷 327-330页

作者： Ying-Ying Han Lan-Juan Zhao Yong Lin Hao He Qing Tian Wei Zhu Hui Shen Xiang-Ding Chen Hong-Wen Deng center of System Biomedical Sciences University of Shanghai for Science and Technology center for bioinformatics and Genomics Department of Global Biostatistics and Data ScienceSchool of Public Health and Tropical MedicineTulane University Laboratory of Molecular and Statistical Genetics and the Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education College of Life SciencesHunan Normal University

Low hip bone mineral density(BMD)is an important index for osteoporosis and is associated with hip fracture,which leads to more cases of disability and mortality than all other kinds of fractures(Kanis et al.,2007).BMD’s heritability is more than 60%(Arden et al.,1996).A number of candidate loci for BMD have been previously identified by Genome Wide Association Studies(GWAS)(Xiong et al.,2009;Karasik et al.,2010;Zhang et al.,2013).Nevertheless,many significant signals based on GWAS are

关键词： BMD ERE is in Multiple analyses indicate the specific association of NR1I3,C6 and TNN with low hip BMD risk of GWAS BRCA NR with

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