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Dynamic DNA methylation reveals novel cis-regulatory elements in mouse hematopoiesis

  • Maximilian Schönung
    Affiliations
    Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany

    Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
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  • Mark Hartmann
    Affiliations
    Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany

    Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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  • Stephen Krämer
    Affiliations
    Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany

    Faculty of Biosciences, Heidelberg University, Heidelberg, Germany

    Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Augsburg, Germany
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  • Sina Stäble
    Affiliations
    Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany
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  • Mariam Hakobyan
    Affiliations
    Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany

    Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
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  • Emely Kleinert
    Affiliations
    Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany
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  • Theo Aurich
    Affiliations
    Division of Experimental Hematology, German Cancer Research Center, Heidelberg, Germany

    Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
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  • Defne Cobanoglu
    Affiliations
    Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany

    Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
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  • Florian H. Heidel
    Affiliations
    Innere Medizin C, Universitätsmedizin Greifswald, Greifswald, Germany

    Leibniz Institute on Aging, Fritz-Lipmann-Institute, Jena, Germany
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  • Stefan Fröhling
    Affiliations
    Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany
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  • Michael D. Milsom
    Affiliations
    Division of Experimental Hematology, German Cancer Research Center, Heidelberg, Germany

    Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
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  • Matthias Schlesner
    Affiliations
    Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Augsburg, Germany
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  • Pavlo Lutsik
    Correspondence
    Pavlo Lutsik, Division of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany;
    Affiliations
    Division of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany
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  • Daniel B. Lipka
    Correspondence
    Offprint requests to: Daniel B. Lipka, Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany
    Affiliations
    Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany

    Faculty of Medicine, Otto-von-Guericke-University, Magdeburg, Germany
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Published:November 07, 2022DOI:https://doi.org/10.1016/j.exphem.2022.11.001

      Highlights

      • Generation of a DNA methylation reference map of mouse hematopoiesis.
      • Development of a Mouse Methylation BeadChip array analysis pipeline.
      • Progressive establishment of DNA methylation patterns during hematopoiesis.
      • Discovery of novel DNA methylation-dynamic cis-regulatory elements (novel mdCREs).
      • Association of key hematopoietic lineage genes with hypomethylation of novel mdCREs.
      Differentiation of hematopoietic stem and progenitor cells to terminally differentiated immune cells is accompanied by large-scale remodeling of the DNA methylation landscape. Although significant insights into the molecular mechanisms of hematopoietic tissue regeneration were derived from mouse models, profiling of DNA methylation has been hampered by high cost or low resolution using available methods. The recent development of the Infinium Mouse Methylation BeadChip (MMBC) array facilitates methylation profiling of the mouse genome at a single CpG resolution at affordable cost.
      We extended the RnBeads package to provide a computational framework for the analysis of MMBC data. This framework was applied to a newly generated reference map of mouse hematopoiesis encompassing nine different cell types. Analysis of dynamically regulated CpG sites showed progressive and unidirectional DNA methylation changes from hematopoietic stem and progenitor cells to differentiated hematopoietic cells and allowed the identification of lineage- and cell type–specific DNA methylation programs. Comparison with previously published catalogs of cis-regulatory elements (CREs) revealed 12,856 novel putative CREs that were dynamically regulated by DNA methylation (mdCREs). These mdCREs were predominantly associated with patterns of cell type–specific DNA hypomethylation and could be identified as epigenetic control regions regulating the expression of key hematopoietic genes during differentiation.
      In summary, we established an analysis pipeline for MMBC data sets and provide a DNA methylation atlas of mouse hematopoiesis. This resource allowed us to identify novel putative CREs involved in hematopoiesis and will serve as a platform to study epigenetic regulation of normal and malignant hematopoiesis.

      Graphical Abstract

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