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

Jason D Buenrostro; M Ryan Corces; Caleb A Lareau; Beijing Wu; Alicia N Schep; Martin J Aryee; Ravindra Majeti; Howard Y Chang; William J Greenleaf

doi:10.1016/j.cell.2018.03.074

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

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

Authors

Jason D Buenrostro¹, M Ryan Corces², Caleb A Lareau³, Beijing Wu⁴, Alicia N Schep⁴, Martin J Aryee⁵, Ravindra Majeti⁶, Howard Y Chang⁷, William J Greenleaf⁸

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Cell Lineage
Chromatin / chemistry*
Epigenesis, Genetic
Epigenomics
Gene Expression Regulation*
Hematopoiesis
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells / cytology*
Humans
Myeloid Progenitor Cells / cytology
Principal Component Analysis
Regulatory Sequences, Nucleic Acid
Sequence Analysis, RNA
Single-Cell Analysis*
Transcription Factors / metabolism*
Transcriptome

Substances

Chromatin
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding