[Spatial Organization of Chromatin of the KLF5 Gene Promoter Region in Pancreatic Ductal Adenocarcinoma Cells].

Abstract

Pancreatic Ductal AdenoCarcinoma (PDAC) is characterized by a poor prognosis and is poorly amenable to modern therapies. A range of cell cultures reflecting different degrees of tumor differentiation and malignancy can serve as a model of PDAC development. Highly differentiated cells with low malignancy are characterized by increased expression of the KLF5 gene. The KLF5 protein is a vivid representative of multifunctional transcription factors, and its involvement in a variety of cellular processes, particularly in the pathology of various cancers, has been demonstrated. We investigated the spatial organization of chromatin of the regulatory regions of the KLF5 gene using highly differentiated Capan2 PDAC cells with a high level of KLF5 expression and poorly differentiated MIA PaCa2 PDAC cells with a low level of expression of this gene by circular chromosome conformation capture (4C-seq). It was shown that the number and distribution of contacts of the KLF5 regulatory region with other chromatin regions are significantly different for these types of cells; the number of contacts is significantly higher for Capan2 cells. There is a correlation between the expression level of genes close to KLF5 and the intensity of their sequence contacts with the KLF5 regulatory region, indicating that their expression is coordinated, possibly within the transcriptional factory. Capan2 is characterized by a high level of contacts of the KLF5 regulatory region with the gene-free region containing a cluster of PDAC-associated single nucleotide polymorphisms (SNP/InDel). Thus, the total number of contacts of the promoter region of the KLF5 gene and the expression level of most of the surrounding KLF5 genes decrease as the grade of cell malignancy increases.