1. Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition
- Author
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Liwen Zhang, Haiyue Liu, Mengzhu Xue, Chang Hongyuan, Peng Wang, Yuwei Liu, and Shaowei Du
- Subjects
0301 basic medicine ,BRD4 ,Epithelial-Mesenchymal Transition ,Lung Neoplasms ,JUNB ,Adenocarcinoma of Lung ,Antineoplastic Agents ,Cell Cycle Proteins ,Biology ,Adenocarcinoma ,Proto-Oncogene Protein c-ets-2 ,Histones ,03 medical and health sciences ,Transforming Growth Factor beta ,Cell Line, Tumor ,Genetics ,Humans ,Epithelial–mesenchymal transition ,Smad3 Protein ,RNA, Small Interfering ,Transcription factor ,Regulation of gene expression ,Sequence Analysis, RNA ,Gene Expression Profiling ,Nuclear Proteins ,Computational Biology ,Epithelial Cells ,Transforming growth factor beta ,Azepines ,Triazoles ,Phenotype ,Survival Analysis ,Cell biology ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Hepatocyte Nuclear Factor 4 ,embryonic structures ,Cancer research ,biology.protein ,Transcriptome ,Signal Transduction ,Transcription Factors - 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.
- Published
- 2016