Single-cell profiling of small molecule-genomic interactions and epigenetic states

Abstract We present scEpiChem, a unique method to jointly measure the genomic interactions of small molecules and epigenetic states, such as histone modifications and chromatin accessibility, within single cells. scEpiChem utilizes split-pool barcoding strategy and protein A-Tn5 (PAT)-anti-biotin antibody to capture biotinylated small molecule binding sites within individual cells. Through sequential targeted tagmentation by different PAT-antibody complexes or Tn5, scEpiChem allows for the simultaneous detection of small molecule drug-target engagement and multimodal epigenome. The efficacy of the protocol is demonstrated through the profiling of biotinylated inhibitors JQ1, THZ1, and Dox. This approach provides valuable insights into cell state-specific drug targeting and gene regulation, facilitating the development of precise therapeutic interventions and the exploitation of drug resistance mechanisms.