DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation
Matthias Farlik 1, 13, Florian Halbritter 1, 13, Fabian Müller 2, 3, 13, Fizzah A. Choudry 4, 5, Peter Ebert 2, 3, Johanna Klughammer 1, Samantha Farrow 4, 5, Antonella Santoro 6, Valerio Ciaurro 6, Anthony Mathur 7, Rakesh Uppal 7, Hendrik G. Stunnenberg 8, Willem H. Ouwehand 4, 5, 9, 10, Elisa Laurenti 4, 6, Thomas Lengauer 2, Mattia Frontini 4, 5, 9, Christoph Bock 1, 2, 11, 12, 14.
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
3 Graduate School of Computer Science, Saarland University, 66123 Saarbrücken, Germany
4 Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK
5 National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
6 Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Clifford Allbutt Building, Hills Road, Cambridge CB2 0AH, UK
7 Department of Cardiology, Barts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS Trust, London EC1A 7BE, UK
8 Faculty of Science, Department of Molecular Biology, Radboud University, 6525GA Nijmegen, the Netherlands
9 British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0QQ, UK
10 Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK
11 Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
12 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, 1090 Vienna, Austria
Received 19 February 2016, Revised 4 October 2016, Accepted 24 October 2016, Available online 17 November 2016
Published: November 17, 2016
Open Access funded by Wellcome Trust
Under a Creative Commons license
Source/Fonte: Christoph Bock/CeMM
Highlights
• Sequencing provides DNA methylation maps of hematopoietic stem and progenitor cells
• Methylation differs in HSCs from fetal liver, bone marrow, cord, and peripheral blood
• Myeloid and lymphoid progenitors are distinguished by enhancer-linked DNA methylation
• Machine learning enables data-driven reconstruction of the hematopoietic lineage
Summary
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.
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