Characterization of transcription factors controlling exocrine pancreas lineages and their role in pancreatic ductal adenocarcinoma

Authors

• MT Ioh
• MM Jezek
• S Baek
• TN Truong Vo
• L Wang
• HE Arda

Abstract

The human pancreas is a complex organ composed of distinct cell types that function together to regulate glucose metabolism and digestion. Transcription factors (TFs) are proteins that bind to enhancers, which together, are responsible for generating diverse cell types and regulating diverse genetic programs. Literature suggests that some TFs can function as master regulators and return cells into progenitor-like states. TF dysregulation is implicated in diseases including pancreatic ductal adenocarcinoma (PDAC), which originates from the exocrine pancreas. It has been shown that PDAC forms not only from duct cells but also from acinar cells transdifferentiating into duct cell-like states. In addition, the introduction of an acinar-specific TF, PTF1A, was able to reverse tumorigenesis in mice pancreas cells. We hypothesize that exocrine pancreas-specific TFs harbor lineage-specific DNA binding motifs, have regulatory transcriptional activity, and can drive cell-type specific gene expression programs. As a pilot experiment, we are modulating the expression of exocrine pancreas-specific TFs in a duct cell-derived pancreas cancer cell line, PANC1. We have generated overexpression lines for five exocrine pancreas-specific TFs — HNF1B, BHLHA15, PTF1A, RBPJL, and XBP-1. We expect these TFs to bind their cognate motifs and alter gene expression or chromatin accessibility in PANC1 cells. We are performing ChIP-seq, ATAC-seq, and RNA-seq on these cell lines to uncover their specific binding sequences, correlation with open-chromatin regions and their resulting gene expression profiles. These results will provide crucial insights into cell-type specific enhancer regulation mechanisms and their involvement in the healthy and disease states of the human pancreas.

Scientific Focus Area: Genetics and Genomics

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