A Multiplexed System for Quantitative Comparisons of Chromatin Landscapes

Genome-wide profiling of histone modifications can provide systematic insight into the regulatory elements and programs engaged in a given cell type. However, conventional chromatin immunoprecipitation and sequencing (ChIP-seq) does not capture quantitative information on histone modification levels, requires large amounts of starting material, and involves tedious processing of each individual sample. Here, we address these limitations with a technology that leverages DNA barcoding to profile chromatin quantitatively and in multiplexed format. We concurrently map relative levels of multiple histone modifications across multiple samples, each comprising as few as a thousand cells. We demonstrate the technology by monitoring dynamic changes following inhibition of p300, EZH2, or KDM5, by linking altered epigenetic landscapes to chromatin regulator mutations, and by mapping active and repressive marks in purified human hematopoietic stem cells. Hence, this technology enables quantitative studies of chromatin state dynamics across rare cell types, genotypes, environmental conditions, and drug treatments. van Galen et al. introduce an approach for multiplexed ChIP-seq on small cell numbers. The approach allows quantitative comparisons of global and locus-specific histone modification levels. The technology is demonstrated by mapping hematopoietic stem cell chromatin landscapes and quantifying changes in leukemia cells treated with epigenetic inhibitors.