High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer

The dynamic nature of chromatin and transcription plays a critical role in normal differentiation and is expected to contribute to tumor evolution. Studying chromatin heterogeneity with single-cell resolution is mandatory to understand the role of epigenetic plasticity in cancer. Here, we describe a droplet microfluidics system that enables the profiling of chromatin marks of individual cells with an average coverage of up to 10,000 loci per cell. In patient-derived xenograft (PDX) models of breast cancer with acquired drug resistance, single-cell chromatin immunoprecipitation followed by sequencing (scChIP-seq) identified rare populations of cells in untreated, drug-sensitive tumors with chromatin features that match those of resistant cells. Loci depleted for transcriptional repressive mark H3K27me3 included genes know to promote resistance to chemotherapy, highlighting the potential to discover new drug targets. Overall design: Single-cell ChIP-seq and single-cell RNA-seq in patient-derived xenograft models of breast cancer with acquired drug resistance