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Cell Stem Cell. 2016 Dec 1;19(6):808-822. doi: 10.1016/j.stem.2016.10.019. Epub 2016 Nov 17.

DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
2
Max Planck Institute for Informatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany; Graduate School of Computer Science, Saarland University, 66123 Saarbrücken, Germany.
3
Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
4
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Clifford Allbutt Building, Hills Road, Cambridge CB2 0AH, UK.
5
Department of Cardiology, Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London EC1A 7BE, UK.
6
Faculty of Science, Department of Molecular Biology, Radboud University, 6525GA Nijmegen, the Netherlands.
7
Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK; British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0QQ, UK; Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
8
Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Clifford Allbutt Building, Hills Road, Cambridge CB2 0AH, UK.
9
Max Planck Institute for Informatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany.
10
Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK; British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0QQ, UK. Electronic address: mf471@cam.ac.uk.
11
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Max Planck Institute for Informatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany; Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, 1090 Vienna, Austria. Electronic address: cbock@cemm.oeaw.ac.at.

Abstract

Hematopoietic stem cells give rise to all blood cells in a differentiation process that involves widespread epigenome remodeling. Here we present genome-wide reference maps of the associated DNA methylation dynamics. We used a meta-epigenomic approach that combines DNA methylation profiles across many small pools of cells and performed single-cell methylome sequencing to assess cell-to-cell heterogeneity. The resulting dataset identified characteristic differences between HSCs derived from fetal liver, cord blood, bone marrow, and peripheral blood. We also observed lineage-specific DNA methylation between myeloid and lymphoid progenitors, characterized immature multi-lymphoid progenitors, and detected progressive DNA methylation differences in maturing megakaryocytes. We linked these patterns to gene expression, histone modifications, and chromatin accessibility, and we used machine learning to derive a model of human hematopoietic differentiation directly from DNA methylation data. Our results contribute to a better understanding of human hematopoietic stem cell differentiation and provide a framework for studying blood-linked diseases.

KEYWORDS:

DNA methylation profiling; bioinformatic lineage reconstruction; cell type prediction; hematopoietic stem cell differentiation; immature lymphoid progenitors; lymphoid-myeloid lineage commitment; megakaryocyte maturation; reference epigenome mapping; single-cell sequencing; whole genome bisulfite sequencing

PMID:
27867036
PMCID:
PMC5145815
DOI:
10.1016/j.stem.2016.10.019
[Indexed for MEDLINE]
Free PMC Article

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