TY - JOUR T1 - Single-cell epigenomics maps the continuous regulatory landscape of human hematopoietic differentiation JF - bioRxiv DO - 10.1101/109843 SP - 109843 AU - Jason D Buenrostro AU - M Ryan Corces AU - Beijing Wu AU - Alicia N Schep AU - Caleb A Lareau AU - Ravindra Majeti AU - Howard Y. Chang AU - William J. Greenleaf Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/02/21/109843.1.abstract N2 - 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. ER -