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Nat Biotechnol. 2015 Nov;33(11):1165-72. doi: 10.1038/nbt.3383. Epub 2015 Oct 12.

Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state.

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Department of Physics and School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
Epigenomics Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Broad Technology Labs, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.


Chromatin profiling provides a versatile means to investigate functional genomic elements and their regulation. However, current methods yield ensemble profiles that are insensitive to cell-to-cell variation. Here we combine microfluidics, DNA barcoding and sequencing to collect chromatin data at single-cell resolution. We demonstrate the utility of the technology by assaying thousands of individual cells and using the data to deconvolute a mixture of ES cells, fibroblasts and hematopoietic progenitors into high-quality chromatin state maps for each cell type. The data from each single cell are sparse, comprising on the order of 1,000 unique reads. However, by assaying thousands of ES cells, we identify a spectrum of subpopulations defined by differences in chromatin signatures of pluripotency and differentiation priming. We corroborate these findings by comparison to orthogonal single-cell gene expression data. Our method for single-cell analysis reveals aspects of epigenetic heterogeneity not captured by transcriptional analysis alone.

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