title: Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution.
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.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.|Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: M Ryan
authors.initials: MR
authors.lastname: Corces
authors.affiliation: Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.|Department of Genetics, Stanford University, Stanford, California, USA.|Broad Institute of MIT and Harvard, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Buenrostro
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Beijing
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.|Program in Biomedical Informatics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Peyton G
authors.initials: PG
authors.lastname: Greenside
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Chan
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Koenig
authors.affiliation: Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.|Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.|Department of Biology, Stanford University, Stanford, California, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Pritchard
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.|Department of Computer Science, Stanford University, Stanford, California, USA.
authors.forename: Anshul
authors.identifier: 0000-0003-3084-2287
authors.initials: A
authors.lastname: Kundaje
authors.affiliation: Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.|Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenleaf
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
authors.affiliation: Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
mesh_terms: D019070:Cell Lineage; D002843:Chromatin; D002999:Clone Cells; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D038042:Myelopoiesis / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA / Q000379:methods; D014407:Tumor Cells, Cultured
chemical_list: D002843:Chromatin