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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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Genome-wide in vitro and in vivo RNAi screens reveal Fer3 to be an important regulator of kkvtranscription in Drosophila

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Insect Science 2022年第3期29卷 614-630页

作者： Xiangzhao Yue Yongkang Liang Zhishuang Wei Jun Lv Yongjin Cai Xiaobin Fan Wenqing Zhang Jie Chen Guangdong Provincial Key Laboratory of High Technology for Plant Protection Plant Protection Research InstituteGuangdong Academy of Agricultural SciencesGuangzhouChina State Key Laboratory of Biocontrol School of Life SciencesSun Yat-sen UniversityGuangzhouChina College of Life Sciences Shangrao Normal UniversityShangraoJiangxi ProvinceChina

Krotzkopf verkehrt(kkv)is a key enzyme that catalyzes the synthesis of chitin,an important component of the Drosophila epidermis,trachea,and other ***,we report the use of comprehensive RNA interference(RNAi)analyses to search for kkv transcriptional regulators.A cell-based RNAi screen identified 537 candidate kkv regulators on a genome-wide *** use of transgenic Drosophila lines expressing RNAi constructs enabled in vivo validation,and we identified six genes as potential kkv transcriptional *** of the kkvDsRed signal,an in vivo reporter indicating kkv promoter activity,was observed when the expression of Akirin,NFAT,48 related 3(Fer3),or Autophagy-related 101(Atg101)was knocked down in Drosophila at the 3rd-instar larval stage;whereas we observed disoriented taenidial folds on larval tracheae when Lines(lin)or Autophagy-related 3 (Atg3)was knocked down in the ***3,in particular,has been shown to be an important factor in the activation of kkv transcription via specific binding with the kkv *** genes involved in the chitin synthesis pathway were widely affected by the downregulation of ***,Atg101,Atg3,Akirin,Lin,NFAT,Pnr,and Abd-A showed that the potential complex mechanism of kkv transcription is regulated by an interaction network with bithorax complex *** study revealed the hitherto unappreciated diversity of modulators impinging on kkv transcription and opens new avenues in the study of kkv regulation and chitin biosynthesis.

关键词： chitin biosynthesis Fer3 genome-wide RNAi kkv transcriptional regulator

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m4C DNA methylation regulates biosynthesis of daptomycin in Streptomyces roseosporus L30

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Synthetic and Systems Biotechnology 2022年第4期7卷 1013-1023页

作者： Jiao-Le Fang Wen-Li Gao Wei-Feng Xu Zhong-Yuan Lyu Lie Ma Shuai Luo Xin-Ai Chen Xu-Ming Mao Yong-Quan Li Institute of Pharmaceutical Biotechnology Zhejiang University School of MedicineHangzhou310058PR China Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering 310058HangzhouPR China

Despite numerous studies on transcriptional level regulation by single genes in drug producing Actinomyces,the global regulation based on epigenetic modification is not well explored.N4-methylcytosine(m4C),an abundant epigenetic marker in Actinomycetes’genome,but its regulatory mechanism remains *** this study,we identify a m4C methyltransferase(SroLm3)in Streptomyces roseosporus L30 and multi-omics studies were performed and revealed SroLm3 as a global regulator of secondary ***,three BGCs inΔsroLm3 strain exhibited decreased expression compared to wild ***-frame deletion of sroLm3 in *** L30 further revealed its role in enhancing daptomycin *** summary,we characterized a m4C methyltransferase,revealed the function of m4C in secondary metabolism regulation and biosynthesis of red pigment,and mapped a series of novel regulators for daptomycin biosynthesis dominated by m4C *** research further indicated that m4C DNA methylation may contribute to a metabolic switch from primary to secondary metabolism in Actinomyces.

关键词： N4-methylcytosine DNA methyltransferase Daptomycin transcriptional regulator Secondary metabolism

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