Single-cell chromatin profiles reveal a spectrum of stem cell epigenetic states

Chromatin profiling provides a versatile means to chart gene regulatory elements and investigate their mechanisms of regulation. However, current methods yield ensemble profiles that are insensitive to cell-to-cell variation. This is a major limitation as transcriptional states and phenotypes vary markedly across individual cells. Here we combined microfluidics, DNA barcoding and sequencing to profile chromatin at single-cell resolution. We demonstrate the technology by profiling a mixture of ES cells, fibroblasts and hematopoietic progenitors, and deconvoluting in silico high-quality maps for each cell type. We find that regulatory elements differ in their variability, with bivalent promoters showing particularly heterogeneous patterns across single-cells that in contrast with to the relative stability of active promoters and enhancers. Finally, we document a spectrum of ES cell states whose chromatin landscapes exhibit varying degrees of pluripotency and priming signatures. Our study presents an innovative single-cell analysis tool for single-cell analysis, and reveals aspects of epigenetic heterogeneity not be captured by transcriptional analysis alone.