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

Nat Genet
Authors
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.

Year of Publication
2016
Journal
Nat Genet
Volume
48
Issue
10
Pages
1193-203
Date Published
2016 Oct
ISSN
1546-1718
DOI
10.1038/ng.3646
PubMed ID
27526324
PubMed Central ID
PMC5042844
Links
Grant list
R25 CA180993 / CA / NCI NIH HHS / United States
R01 CA188055 / CA / NCI NIH HHS / United States
F31 CA180659 / CA / NCI NIH HHS / United States
P50 HG007735 / HG / NHGRI NIH HHS / United States
T32 HG000044 / HG / NHGRI NIH HHS / United States
T32 GM007790 / GM / NIGMS NIH HHS / United States
UH2 AR067676 / AR / NIAMS NIH HHS / United States