Research Projects

Pharmacoepigenome refers to vast and active non-coding regions of our genome that are involved in adaptive response to xenobiotic stimuli by transcriptional reprogramming. Involvement of epigenetic processes in cancer causation and progression, and their potential reversibility have encouraged development and successful clinical use of epigenetic therapy. However, tumours acquire genetic and epigenetic adaptations to evolve from sensitive to resistant phenotype over time in response to drug challenge. We hypothesize that this transition to resistant state is manifested by drug-induced activation of variant enhancers leading to expression of genes facilitating cancer cells to evade drug-effects. To test this hypothesis, we propose to perform ChIP-seq analysis of histone post-translational modifications that are hallmark of active enhancer (H3K27ac), active promoter (H3K4me3) and Polycomb mediated repression (H3K27me3) using in vitro derived chemoresistance model of small cell lung cancer cell lines. We will annotate variant enhancers using histone H3K27ac ChIP-seq peaks and identify the super-enhancers responsible for expression of important genes involved in chemoresistance. Super-enhancer dependency of these genes can be exploited to develop new therapeutic strategies to overcome drug resistance. We are also generating in-house Doxorubicin-tolerant cells with variable degree of drug sensitivity in vitro and their age-matched untreated controls to capture temporal snapshots of drug-tolerant epigenomic states. By integrating expression profiling and enhancer profiling datasets, we plan to construct gene-enhancer regulatory connections and functionally validate this connectivity by targeted disruption of specific enhancers using CRISPRi -based epigenome editing. We envisage that annotation of pharmacoepigenome will offer a unique ‘molecular signature’ that will define tumour’s response to drug and chart new directions for research towards precision medicine. If successful, this study will generate a comprehensive epigenetic profile of acquired chemoresistance which can be extrapolated to multiple cancer types.