Deciphering drug response and phenotypic heterogeneity of cancer cells using gene ensembles of regulatory units defined by chromatin domains

Abstract

Chromatin is organised in the form of domains known to be insulated from neighbouring regions in the genome. The colocalisation of genes sharing similar functions in the topologically associated domains (TAD) and the orchestration of their activity in cancer-cells and their drug-response have not been comprehensively explored. Here we analyzed patterns in the activity of TADs in cancer-cells along with chromatin interaction profiles to understand their modes of drug-response. Using our approach on the transcriptome of 819 cancer cell lines revealed that for multiple drugs, IC50 values were substantially more correlated with the activity of a few TADs than any of the genes. Such a result signifies the potential utility of TAD activity in highlighting common mechanisms of drug response in spite of heterogeneity in the association of genes with drug-resistance. Further we performed analysis of 9014 cancer sample transcriptomes from 20 cancer types to find the relationship between TAD-activity and survival to highlight context of cause and actionable mechanism for better therapy. Overall our analysis highlighted higher importance and influence of combinatorics of genes in many TADs in comparison to independent effect of their own genes , on the patient-survival and drug-response of cancer-cells.