title: DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation.
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.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Farlik
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Halbritter
authors.affiliation: Max Planck Institute for Informatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany; Graduate School of Computer Science, Saarland University, 66123 Saarbrücken, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
authors.forename: Fizzah A
authors.initials: FA
authors.lastname: Choudry
authors.affiliation: Max Planck Institute for Informatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany; Graduate School of Computer Science, Saarland University, 66123 Saarbrücken, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ebert
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Johanna
authors.initials: J
authors.lastname: Klughammer
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Farrow
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Clifford Allbutt Building, Hills Road, Cambridge CB2 0AH, UK.
authors.forename: Antonella
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Clifford Allbutt Building, Hills Road, Cambridge CB2 0AH, UK.
authors.forename: Valerio
authors.initials: V
authors.lastname: Ciaurro
authors.affiliation: Department of Cardiology, Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London EC1A 7BE, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Department of Cardiology, Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London EC1A 7BE, UK.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Uppal
authors.affiliation: Faculty of Science, Department of Molecular Biology, Radboud University, 6525GA Nijmegen, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: 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.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: 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.
authors.forename: Elisa
authors.initials: E
authors.lastname: Laurenti
authors.affiliation: Max Planck Institute for Informatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.affiliation: 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.
authors.forename: Mattia
authors.initials: M
authors.lastname: Frontini
authors.affiliation: 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.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
mesh_terms: D001665:Binding Sites; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage; D002469:Cell Separation; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D044127:Epigenesis, Genetic; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000196:embryology; D008214:Lymphocytes / Q000166:cytology; D000069550:Machine Learning; D008533:Megakaryocytes / Q000166:cytology; D008938:Mitosis / Q000235:genetics; D039902:Multipotent Stem Cells / Q000166:cytology; D022423:Myeloid Cells / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; D014157:Transcription Factors
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