FOXA2 controls the cis-regulatory networks of pancreatic cancer cells in a differentiation grade-specific manner: EMBO Journal

M. Milan, C. Balestrieri, G. Alfarano, S. Polletti, E. Prosperini, P. Spaggiari, A. Zerbi, G.R. Diaferia, G. Natoli

Research output: Contribution to journalArticle

Abstract

Differentiation of normal and tumor cells is controlled by regulatory networks enforced by lineage-determining transcription factors (TFs). Among them, TFs such as FOXA1/2 bind naïve chromatin and induce its accessibility, thus establishing new gene regulatory networks. Pancreatic ductal adenocarcinoma (PDAC) is characterized by the coexistence of well- and poorly differentiated cells at all stages of disease. How the transcriptional networks determining such massive cellular heterogeneity are established remains to be determined. We found that FOXA2, a TF controlling pancreas specification, broadly contributed to the cis-regulatory networks of PDACs. Despite being expressed in both well- and poorly differentiated PDAC cells, FOXA2 displayed extensively different genomic distributions and controlled distinct gene expression programs. Grade-specific functions of FOXA2 depended on its partnership with TFs whose expression varied depending on the differentiation grade. These data suggest that FOXA2 contributes to the regulatory networks of heterogeneous PDAC cells via interactions with alternative partner TFs. © 2019 The Authors
Original languageEnglish
JournalEMBO Journal
Volume38
Issue number20
DOIs
Publication statusPublished - 2019

Keywords

  • differentiation
  • FOXA2
  • pancreatic cancer
  • transcription
  • transcription factor
  • FOXA1 protein, human
  • FOXA2 protein, human
  • hepatocyte nuclear factor 1beta
  • hepatocyte nuclear factor 3alpha
  • hepatocyte nuclear factor 3beta
  • HNF1B protein, human
  • homeodomain protein
  • HOXB8 protein, human
  • apoptosis
  • Article
  • cell adhesion
  • cell differentiation
  • cell migration
  • cell proliferation
  • controlled study
  • epithelial mesenchymal transition
  • FOXA1 gene
  • FOXA2 gene
  • gene
  • gene control
  • gene expression
  • gene knockout
  • gene regulatory network
  • genomics
  • human
  • human cell
  • pancreas adenocarcinoma
  • pancreatic cancer cell line
  • phenotype
  • priority journal
  • cancer grading
  • cell motion
  • gene expression regulation
  • genetics
  • metabolism
  • pancreas carcinoma
  • pancreas tumor
  • pathology
  • regulatory sequence
  • tumor cell culture
  • Carcinoma, Pancreatic Ductal
  • Cell Differentiation
  • Cell Movement
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Hepatocyte Nuclear Factor 1-beta
  • Hepatocyte Nuclear Factor 3-alpha
  • Hepatocyte Nuclear Factor 3-beta
  • Homeodomain Proteins
  • Humans
  • Neoplasm Grading
  • Pancreatic Neoplasms
  • Regulatory Elements, Transcriptional
  • Tumor Cells, Cultured

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