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.
Bibliographical noteFunding Information:
We thank D. Flowers and I. Bernstein for providing test samples; R. Nicol, A. Gerard, and A. Kreso for helpful suggestions and comments; and J.D. Jaffe for sharing mass spectrometry data. This research was supported by funds from the National Human Genome Research Institute (HG006991 and HG006193), the National Heart Lung and Blood Institute (U01HL100395), the Howard Hughes Medical Institute, EMBO Fellowships (P.v.G. ALTF 1207- 2014 and C.S. ALTF 654-2014), and a Damon Runyon Postdoctoral Fellowship (A.D.V.). B.E.B. is an American Cancer Society Research Professor.
© 2016 Elsevier Inc.