1. Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma
- Author
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Chen, Li, Huang, Moli, Plummer, Jasmine, Pan, Jian, Jiang, Yan Yi, Yang, Qian, Silva, Tiago Chedraoui, Gull, Nicole, Chen, Stephanie, Ding, Ling Wen, An, Omer, Yang, Henry, Cheng, Yulan, Said, Jonathan W, Doan, Ngan, Dinjens, Winand NM, Waters, Kevin M, Tuli, Richard, Gayther, Simon A, Klempner, Samuel J, Berman, Benjamin P, Meltzer, Stephen J, Lin, De-Chen, and Koeffler, H Phillip
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Human Genome ,Genetics ,Rare Diseases ,1.1 Normal biological development and functioning ,Aetiology ,2.1 Biological and endogenous factors ,Underpinning research ,Adenocarcinoma ,Case-Control Studies ,Cell Line ,Tumor ,Cell Proliferation ,DNA-Binding Proteins ,Esophageal Neoplasms ,Esophageal Squamous Cell Carcinoma ,GATA6 Transcription Factor ,Gene Regulatory Networks ,Humans ,Kruppel-Like Transcription Factors ,Proto-Oncogene Proteins c-ets ,Transcription Factors ,gene regulation ,oesophageal cancer ,signal transduction ,transcription factor ,Clinical Sciences ,Paediatrics and Reproductive Medicine ,Gastroenterology & Hepatology ,Clinical sciences ,Nutrition and dietetics - Abstract
ObjectiveWhile oesophageal squamous cell carcinoma remains infrequent in Western populations, the incidence of oesophageal adenocarcinoma (EAC) has increased sixfold to eightfold over the past four decades. We aimed to characterise oesophageal cancer-specific and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs). DESIGN: To identify regulatory elements, we profiled fresh-frozen oesophageal normal samples, tumours and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modelling was performed to establish (super)-enhancers landscapes and interconnected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs were investigated by ChIP-Seq, circularised chromosome conformation capture sequencing and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo.ResultsWe found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of oesophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signalling pathways, some of which may be exploited pharmacologically (eg, leukemia inhibitory factor (LIF) pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by four master TFs-ELF3, KLF5, GATA6 and EHF-which promoted each other's expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival.ConclusionsBy establishing cancer-specific and subtype-specific features of the EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.
- Published
- 2020