Investigating the chromatin‐modulated transcriptional response of cancer cells to drug treatment

Abstract

Macromolecular crowding within the nucleus contributes to heterogeneity in chromatin packing and thus plays an important role in the regulation of gene expression. Nuclear crowding models predict that a change in chromatin structure will affect gene accessibility and transcription, which may have important functional consequences in cellular stress response. Since these studies have focused on ovarian adenocarcinoma, we aim to determine whether this theory can be extended to other types of cancer. Using differential gene expression analysis on bulk RNA‐sequencing data and partial wave spectroscopic (PWS) microscopy imaging of colon and mutant ovarian cancer cell lines, we see that the impact of crowding and chromatin packing on transcription can be extended to other cancer types. Comparison of these results with predictions from the chromatin packing‐macromolecular crowding model (CPMC), which relates physical changes in chromatin structure to changes in gene expression patterns, further showed that the complex bidirectional response of transcription to crowding is not cell‐line specific. Additionally, we show that the transcriptional response changes when the cellular stressor is a chemotherapeutic agent rather than a benign ion modulating compound. The results have important implications in understanding the role of chromatin structure in cellular stress response and drug resistance in cancer.