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Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Human Developmental Hematopoiesis.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Ranzoni, Anna Maria 
Tangherloni, Andrea 
Berest, Ivan 
Riva, Simone Giovanni 
Myers, Brynelle 

Abstract

Regulation of hematopoiesis during human development remains poorly defined. Here we applied single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to over 8,000 human immunophenotypic blood cells from fetal liver and bone marrow. We inferred their differentiation trajectory and identified three highly proliferative oligopotent progenitor populations downstream of hematopoietic stem cells (HSCs)/multipotent progenitors (MPPs). Along this trajectory, we observed opposing patterns of chromatin accessibility and differentiation that coincided with dynamic changes in the activity of distinct lineage-specific transcription factors. Integrative analysis of chromatin accessibility and gene expression revealed extensive epigenetic but not transcriptional priming of HSCs/MPPs prior to their lineage commitment. Finally, we refined and functionally validated the sorting strategy for the HSCs/MPPs and achieved around 90% enrichment. Our study provides a useful framework for future investigation of human developmental hematopoiesis in the context of blood pathologies and regenerative medicine.

Description

Keywords

bone marrow, fetal hematopoiesis, fetal liver, hematopoietic stem cells, scATAC-seq, scRNA-seq, Cell Lineage, Chromatin Immunoprecipitation Sequencing, Hematopoiesis, Hematopoietic Stem Cells, Humans, RNA-Seq, Single-Cell Analysis

Journal Title

Cell Stem Cell

Conference Name

Journal ISSN

1934-5909
1875-9777

Volume Title

28

Publisher

Elsevier BV
Sponsorship
European Research Council (677501)
Wellcome Trust (203151/Z/16/Z)
Medical Research Council (MC_PC_12009)
Medical Research Council (MC_PC_17230)
Medical Research Council (MR/M008975/1)
The study was supported by European Research Council project 677501 – ZF_Blood (to A.C. and A.M.R), EMBO small grant (to A.C.) and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute.