Abstract
We define the chromatin accessibility and transcriptional landscapes in thirteen human primary blood cell types that traverse 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 reveal the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia (AML), chromatin accessibility reveals unique regulatory evolution in cancer cells with progressive mutation burden. Single AML cells exhibit distinctive mixed regulome profiles of disparate developmental stages. A method to account for this regulatory heterogeneity identified cancer-specific deviations and implicated HOX factors as key regulators of pre-leukemic HSC characteristics. Thus, regulome dynamics can provide diverse insights into hematopoietic development and disease.
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