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Single-cell epigenomics maps the continuous regulatory landscape of human hematopoietic differentiation

View ORCID ProfileJason D Buenrostro, M Ryan Corces, Beijing Wu, Alicia N Schep, Caleb A Lareau, Ravindra Majeti, Howard Y. Chang, William J. Greenleaf
doi: https://doi.org/10.1101/109843
Jason D Buenrostro
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
2Harvard Society of Fellows, Harvard University, Cambridge, MA 02138, USA
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  • ORCID record for Jason D Buenrostro
M Ryan Corces
3Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305
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Beijing Wu
4Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA School of Medicine, Stanford, CA 94305, USA
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Alicia N Schep
4Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA School of Medicine, Stanford, CA 94305, USA
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Caleb A Lareau
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Ravindra Majeti
5Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
6Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
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Howard Y. Chang
3Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305
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William J. Greenleaf
3Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305
4Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA School of Medicine, Stanford, CA 94305, USA
7Department of Applied Physics, Stanford University, Stanford, CA 94025, USA
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Abstract

Normal human hematopoiesis involves cellular differentiation of multipotent cells into progressively more lineage-restricted states. While epigenomic landscapes of this process have been explored in immunophenotypically-defined populations, the single-cell regulatory variation that defines hematopoietic differentiation has been hidden by ensemble averaging. We generated single-cell chromatin accessibility landscapes across 8 populations of immunophenotypically-defined human hematopoietic cell types. Using bulk chromatin accessibility profiles to scaffold our single-cell data analysis, we constructed an epigenomic landscape of human hematopoiesis and characterized epigenomic heterogeneity within phenotypically sorted populations to find epigenomic lineage-bias toward different developmental branches in multipotent stem cell states. We identify and isolate sub-populations within classically-defined granulocyte-macrophage progenitors (GMPs) and use ATAC-seq and RNA-seq to confirm that GMPs are epigenomically and transcriptomically heterogeneous. Furthermore, we identified transcription factors and cis-regulatory elements linked to changes in chromatin accessibility within cellular populations and across a continuous myeloid developmental trajectory, and observe relatively simple TF motif dynamics give rise to a broad diversity of accessibility dynamics at cis-regulatory elements. Overall, this work provides a template for exploration of complex regulatory dynamics in primary human tissues at the ultimate level of granular specificity – the single cell.

One Sentence Summary Single cell chromatin accessibility reveals a high-resolution, continuous landscape of regulatory variation in human hematopoiesis.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 21, 2017.
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Single-cell epigenomics maps the continuous regulatory landscape of human hematopoietic differentiation
Jason D Buenrostro, M Ryan Corces, Beijing Wu, Alicia N Schep, Caleb A Lareau, Ravindra Majeti, Howard Y. Chang, William J. Greenleaf
bioRxiv 109843; doi: https://doi.org/10.1101/109843
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Single-cell epigenomics maps the continuous regulatory landscape of human hematopoietic differentiation
Jason D Buenrostro, M Ryan Corces, Beijing Wu, Alicia N Schep, Caleb A Lareau, Ravindra Majeti, Howard Y. Chang, William J. Greenleaf
bioRxiv 109843; doi: https://doi.org/10.1101/109843

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