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      Integrated single-cell analysis maps the continuous regulatory landscape of human hematopoietic differentiation

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          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 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.

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          Author and article information

          Journal
          0413066
          2830
          Cell
          Cell
          Cell
          0092-8674
          1097-4172
          25 May 2018
          26 April 2018
          31 May 2018
          31 May 2019
          : 173
          : 6
          : 1535-1548.e16
          Affiliations
          [1 ]Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
          [2 ]Harvard Society of Fellows, Harvard University, Cambridge, MA 02138, USA.
          [3 ]Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
          [4 ]Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. School of Medicine, Stanford, CA 94305, USA.
          [5 ]Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
          [6 ]Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
          [7 ]Department of Applied Physics, Stanford University, Stanford, CA 94025, USA.
          [8 ]Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
          Author notes
          Article
          PMC5989727 PMC5989727 5989727 nihpa963511
          10.1016/j.cell.2018.03.074
          5989727
          29706549
          5d236c3a-a282-43be-9959-5304e6b813c1
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