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bioRxiv · 10.1101/109843

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

Buenrostro, J. D.·Greenleaf, W.·Corces, R.·Wu, B.·Schep, A. N.·Lareau, C.·Majeti, R.·Chang, H.
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Abstract

AbstractNormal 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.\n\nOne Sentence SummarySingle cell chromatin accessibility reveals a high-resolution, continuous landscape of regulatory variation in human hematopoiesis.

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Buenrostro, J. D., Greenleaf, W., Corces, R., Wu, B., Schep, A. N., Lareau, C., Majeti, R., Chang, H.. 2017-02-21. Single-cell epigenomics maps the continuous regulatory landscape of human hematopoietic differentiation. https://doi.org/10.1101/109843

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