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

• Published in: Nature genetics Vol. 48; no. 10; pp. 1193 - 1203
• Main Authors: Corces, M Ryan, Buenrostro, Jason D, Wu, Beijing, Greenside, Peyton G, Chan, Steven M, Koenig, Julie L, Snyder, Michael P, Pritchard, Jonathan K, Kundaje, Anshul, Greenleaf, William J, Majeti, Ravindra, Chang, Howard Y
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2016; Nature Publishing Group
• Subjects: 45/100; 45/91; 631/208; 631/208/212; 631/532; 631/67/1990/283/1897; Agriculture; Animal Genetics and Genomics; Biomedicine; Blood; Cancer; Cancer Research; Cell Lineage; Chromatin; Classification; Clone Cells; Developmental stages; Disease susceptibility; Enhancer Elements, Genetic; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Function; Genetic aspects; Genomes; Hematopoiesis - genetics; Hematopoietic stem cells; Heterogeneity; Human Genetics; Humans; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Methods; Mutation; Myelopoiesis - genetics; Regulatory Sequences, Nucleic Acid; RNA; Sequence Analysis, DNA - methods; Stem cells; Studies; Transcription (Genetics); Tumor Cells, Cultured
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3646

Howard Chang, Ravindra Majeti and colleagues define the chromatin accessibility and transcriptional landscapes in 13 human primary blood cell types and in acute myeloid leukemia cells. They identify potential regulators governing hematopoietic differentiation and genetic elements linked to regulatory evolution in cancer cells. 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.