Deciphering the phenotypic heterogeneity and drug response in cancer cells using activity and interactions in chromatin domains

Abstract

AbstractThe effect of colocalization of genes in the topologically associated domains (TADs) and their activity orchestration in cancer samples and cells, hand-in-hand with drug-response have not been comprehensively studied. Here, we analyzed patterns in the activity of TADs in cancer-cells along with chromatin interaction profiles to understand their modes of drug-response. Analysis of transcriptomes of 819 cancer cell lines revealed that their response to multiple drugs were more correlated with the activity of TADs than individual genes. Applying our approach to 9014 cancer patients’ data of 20 different cancer-types further strengthened the association between drug response and the activity of TADs, instead of individual genes, highlighting similarity despite cancer heterogeneity. CRISPR-mediated knock-out of regulatory sites inside a TAD associated with cisplatin-response of oral cancer cells and discovery of primate-specific gain of synteny of genes within a TAD containing EGFR gene and its consequence, also demonstrate greater utility of TAD-activity based analysis.