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Cell. 2018 May 31;173(6):1535-1548.e16. doi: 10.1016/j.cell.2018.03.074. Epub 2018 Apr 26.

Integrated Single-Cell Analysis Maps the Continuous Regulatory Landscape of Human Hematopoietic Differentiation.

Author information

1
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Society of Fellows, Harvard University, Cambridge, MA 02138, USA. Electronic address: jbuen@broadinstitute.org.
2
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
3
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
4
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02115, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
6
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford 94305, CA, USA.
7
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
8
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Applied Physics, Stanford University, Stanford, CA 94025, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: wjg@stanford.edu.

Abstract

Human hematopoiesis involves cellular differentiation of multipotent cells into progressively more lineage-restricted states. While the chromatin accessibility landscape of this process has been explored in defined populations, single-cell regulatory variation has been hidden by ensemble averaging. We collected single-cell chromatin accessibility profiles across 10 populations of immunophenotypically defined human hematopoietic cell types and constructed a chromatin accessibility landscape of human hematopoiesis to characterize differentiation trajectories. We find variation consistent with lineage bias toward different developmental branches in multipotent cell types. We observe heterogeneity within common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) and develop a strategy to partition GMPs along their differentiation trajectory. Furthermore, we integrated single-cell RNA sequencing (scRNA-seq) data to associate transcription factors to chromatin accessibility changes and regulatory elements to target genes through correlations of expression and regulatory element accessibility. Overall, this work provides a framework for integrative exploration of complex regulatory dynamics in a primary human tissue at single-cell resolution.

KEYWORDS:

chromatin accessibility; epigenomics; hematopoiesis; single cell

PMID:
29706549
PMCID:
PMC5989727
[Available on 2019-05-31]
DOI:
10.1016/j.cell.2018.03.074

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