High-Resolution Characterization of Drug-Induced Cellular Response
Andrew T. Kwon1, Masaaki Furuno1, Takahiro Arakawa1, Satoshi Takizawa1, Efthymios Motakis1, Yi Huang1, Harukazu Suzuki1, Erik Arner1*
1RIKEN Center for Life Science Technologies
For drug mode of action analysis and repositioning, drug response expression profiling has emerged as a powerful technique as it allows us to characterize the cellular response to drug treatments at a molecular level. However, existing approaches and resources are limited by their low resolution at genomic, cell state, and cell type levels, as they rely on existing gene models and cannot adequately deal with cellular heterogeneity. With the single cell, high throughput transcriptomic approach, we can overcome these resolution limitations of both the genomic and cellular level. Not only can we examine both existing and novel promoters, enhancers, and lncRNA, but also resolve the minute differences in cellular make up and their internal states. Thus, by measuring gene expression levels using single cell sequencing methods in an unbiased manner, we can assess the effects of population heterogeneity on their response to drugs, and perform a more detailed mode of action analysis. In this study, we profile drug response in 3 different cell lines (fibroblasts, MCF7, and HepG2) to 2 different classes of drugs (statins and histone deacetylase inhibitors) using the newly developed C1 CAGE method, which can robustly detect the expression of individual promoters and enhancers at a genome-wide scale, in a single experiment. We identify and characterize the sub-populations of these cells based on their differential response to drug treatments.