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Nat Genet. 2016 Oct;48(10):1193-203. doi: 10.1038/ng.3646. Epub 2016 Aug 15.

Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution.

Author information

1
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
2
Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
3
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
4
Department of Genetics, Stanford University, Stanford, California, USA.
5
Broad Institute of MIT and Harvard, Harvard University, Cambridge, Massachusetts, USA.
6
Program in Biomedical Informatics, Stanford University School of Medicine, Stanford, California, USA.
7
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
8
Department of Biology, Stanford University, Stanford, California, USA.
9
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
10
Department of Computer Science, Stanford University, Stanford, California, USA.

Abstract

We define the chromatin accessibility and transcriptional landscapes in 13 human primary blood cell types that span the hematopoietic hierarchy. Exploiting the finding that the enhancer landscape better reflects cell identity than mRNA levels, we enable 'enhancer cytometry' for enumeration of pure cell types from complex populations. We identify regulators governing hematopoietic differentiation and further show the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia (AML), chromatin accessibility uncovers unique regulatory evolution in cancer cells with a progressively increasing mutation burden. Single AML cells exhibit distinctive mixed regulome profiles corresponding to disparate developmental stages. A method to account for this regulatory heterogeneity identified cancer-specific deviations and implicated HOX factors as key regulators of preleukemic hematopoietic stem cell characteristics. Thus, regulome dynamics can provide diverse insights into hematopoietic development and disease.

PMID:
27526324
PMCID:
PMC5042844
DOI:
10.1038/ng.3646
[Indexed for MEDLINE]
Free PMC Article

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