title: Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition.
abstract: Epithelial-to-mesenchymal transition (EMT) is a complex multistep process in which phenotype switches are mediated by a network of transcription factors (TFs). Systematic characterization of all dynamic TFs controlling EMT state transitions, especially for the intermediate partial-EMT state, represents a highly relevant yet largely unexplored task. Here, we performed a computational analysis that integrated time-course EMT transcriptomic data with public cistromic data and identified three synergistic master TFs (ETS2, HNF4A and JUNB) that regulate the transition through the partial-EMT state. Overexpression of these regulators predicted a poor clinical outcome, and their elimination readily abolished TGF-β-induced EMT. Importantly, these factors utilized a clique motif, physically interact and their cumulative binding generally characterized EMT-associated genes. Furthermore, analyses of H3K27ac ChIP-seq data revealed that ETS2, HNF4A and JUNB are associated with super-enhancers and the administration of BRD4 inhibitor readily abolished TGF-β-induced EMT. These findings have implications for systematic discovery of master EMT regulators and super-enhancers as novel targets for controlling metastasis.
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, 100 Haike Road, Zhangjiang High-Tech Park, Shanghai 201210, PR China University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China.
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Chang
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, 100 Haike Road, Zhangjiang High-Tech Park, Shanghai 201210, PR China.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, 100 Haike Road, Zhangjiang High-Tech Park, Shanghai 201210, PR China.
authors.forename: Mengzhu
authors.initials: M
authors.lastname: Xue
authors.affiliation: University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, PR China.
authors.forename: Haiyue
authors.initials: H
authors.lastname: Liu
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, 100 Haike Road, Zhangjiang High-Tech Park, Shanghai 201210, PR China School of Life Sciences, Shanghai University, 333 Nanchen Road, Shanghai 200444, PR China.
authors.forename: Shaowei
authors.initials: S
authors.lastname: Du
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, 100 Haike Road, Zhangjiang High-Tech Park, Shanghai 201210, PR China University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang High-Tech Park, Shanghai 201203, PR China School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Zhangjiang High-Tech Park, Shanghai 201210, PR China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, 100 Haike Road, Zhangjiang High-Tech Park, Shanghai 201210, PR China University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Zhangjiang High-Tech Park, Shanghai 201210, PR China wangpeng@sari.ac.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051557:Hepatocyte Nuclear Factor 4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D050787:Proto-Oncogene Protein c-ets-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D051557:Hepatocyte Nuclear Factor 4; D006657:Histones; D009687:Nuclear Proteins; D050787:Proto-Oncogene Protein c-ets-2; D034741:RNA, Small Interfering; D051900:Smad3 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C494069:ETS2 protein, human; C496592:HNF4A protein, human; C581727:JunB protein, human; C497790:SMAD3 protein, human