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 naive 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.

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

Zerbi, Alessandro;Natoli, Gioacchino
2019

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 naive 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.
FOXA2
differentiation
pancreatic cancer
transcription
Carcinoma, Pancreatic Ductal
Cell Movement
Cell Proliferation
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
Tumor Cells, Cultured
Cell Differentiation
Gene Expression Regulation, Neoplastic
Regulatory Elements, Transcriptional
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/59349
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