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DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease

Melinda Czeh, Sina Stäble, Stephen Krämer, Lena Tepe, Sweta Talyan, Joana Carrelha, Yiran Meng, Barbara Heitplatz, Marius Schwabenland, Michael D. Milsom, Christoph Plass, Marco Prinz, Matthias Schlesner, Miguel A. Andrade-Navarro, Claus Nerlov, Sten Eirik W. Jacobsen, Daniel B. Lipka and Frank Rosenbauer
J Immunol January 15, 2022, 208 (2) 358-370; DOI: https://doi.org/10.4049/jimmunol.2100624
Melinda Czeh
*Institute of Molecular Tumor Biology, University of Münster, Münster, Germany;
†MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK;
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Sina Stäble
‡Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases Heidelberg, Heidelberg, Germany;
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Stephen Krämer
‡Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases Heidelberg, Heidelberg, Germany;
§Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Germany;
¶Bioinformatics and Omics Data Analysis, German Cancer Research Center, Heidelberg, Germany;
‖Faculty of Biosciences, Heidelberg University, Heidelberg, Germany;
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Lena Tepe
*Institute of Molecular Tumor Biology, University of Münster, Münster, Germany;
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Sweta Talyan
#Faculty of Biology, Johannes Gutenberg University of Mainz, Mainz, Germany;
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  • ORCID record for Sweta Talyan
Joana Carrelha
†MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK;
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Yiran Meng
†MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK;
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Barbara Heitplatz
**Gerhard-Domagk-Institute of Pathology, University Hospital Münster, University of Münster, Münster, Germany;
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Marius Schwabenland
††Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany;
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Michael D. Milsom
‡‡Division of Experimental Hematology, German Cancer Research Center, Heidelberg, Germany;
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Christoph Plass
§§Division of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany;
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Marco Prinz
††Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany;
¶¶Centre for Biological Signalling Studies and Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany;
‖‖Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany;
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Matthias Schlesner
§Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Germany;
¶Bioinformatics and Omics Data Analysis, German Cancer Research Center, Heidelberg, Germany;
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Miguel A. Andrade-Navarro
#Faculty of Biology, Johannes Gutenberg University of Mainz, Mainz, Germany;
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Claus Nerlov
†MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK;
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Sten Eirik W. Jacobsen
†MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK;
##Department of Cell and Molecular Biology and Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden; and
***Karolinska University Hospital, Stockholm, Sweden
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Daniel B. Lipka
‡Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center and National Center for Tumor Diseases Heidelberg, Heidelberg, Germany;
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Frank Rosenbauer
*Institute of Molecular Tumor Biology, University of Münster, Münster, Germany;
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Key Points

  • Myeloid-restricted hematopoietic stem cells can replenish pDC and cDC in vivo.

  • DC diversification is associated with differences in genomic methylation levels.

  • Reducing Dnmt1 activity alleviates systemic lupus erythematosus autoimmunity.

Abstract

Dendritic cells (DCs) are heterogeneous immune regulators involved in autoimmune diseases. Epigenomic mechanisms orchestrating DC development and DC subset diversification remain insufficiently understood but could be important to modulate DC fate for clinical purposes. By combining whole-genome methylation assessment with the analysis of mice expressing reduced DNA methyltransferase 1 levels, we show that distinct DNA methylation levels and patterns are required for the development of plasmacytoid DC and conventional DC subsets. We provide clonal in vivo evidence for DC lineage establishment at the stem cell level, and we show that a high DNA methylation threshold level is essential for Flt3-dependent survival of DC precursors. Importantly, reducing methylation predominantly depletes plasmacytoid DC and alleviates systemic lupus erythematosus in an autoimmunity mouse model. This study shows how DNA methylation regulates the production of DC subsets and provides a potential rationale for targeting autoimmune disease using hypomethylating agents.

This article is featured in Top Reads, p.

Footnotes

  • This work was supported by a fellowship from Cancer Research UK (A24872) and an institutional grant from the University of Münster medical faculty (IMF, CZ121523) to M.C., by an international recruitment grant from The Swedish Research Council (538-2013-8995) and The Medical Research Council (MC_UU_12009/5) to S.E.W.J., by a Cancer Transitional Research and Exchange Program Ph.D.-to-Postdoctoral Fellowship to S.S., by institutional funds and grants from the Deutsche Krebshilfe (DKH 70112574) to D.B.L., by the Deutsche Forschungsgemeinschaft (DFG) research unit FOR 2674 to M.D.M., C.P., and D.B.L., and by DFG grants (RO 2295/5-1 and RO 2295/5-2) and institutional funds to F.R.

  • M.C., S.S., J.C., Y.M., and L.T. performed experiments, S.K., S.T., M. Schlesner, and M.A.A.-N. conducted computational data analyses, B.H., M. Schwabenland, and M.P. performed histological analyses, M.D.M., C.P., C.N., S.E.W.J., D.B.L., and F.R. designed the research and analyzed data. M.C., D.B.L., and F.R. wrote the manuscript.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    BM
    bone marrow
    cDC
    conventional DC
    CDP
    common DC progenitor
    cMoP
    common monocyte progenitor
    DC
    dendritic cell
    DMR
    differentially methylated region
    DNMT
    DNA methyltransferase
    HSC
    hematopoietic stem cell
    LSK
    CD45.2+Lin−Sca-1+Kit+
    MDP
    macrophage–DC progenitor
    MHCII
    MHC class II
    P
    platelet
    PAS
    periodic acid–Schiff reaction
    PCA
    principal component analysis
    pDC
    plasmacytoid DC
    PEM
    P–erythrocyte–myeloid
    PEM-B
    PEM–B lymphoid
    SLE
    systemic lupus erythematosus
    TWGBS
    tagmentation-based whole-genome bisulfite sequencing

  • Received June 25, 2021.
  • Accepted October 28, 2021.
  • Copyright © 2022 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (2)
The Journal of Immunology
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15 Jan 2022
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DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease
Melinda Czeh, Sina Stäble, Stephen Krämer, Lena Tepe, Sweta Talyan, Joana Carrelha, Yiran Meng, Barbara Heitplatz, Marius Schwabenland, Michael D. Milsom, Christoph Plass, Marco Prinz, Matthias Schlesner, Miguel A. Andrade-Navarro, Claus Nerlov, Sten Eirik W. Jacobsen, Daniel B. Lipka, Frank Rosenbauer
The Journal of Immunology January 15, 2022, 208 (2) 358-370; DOI: 10.4049/jimmunol.2100624

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DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease
Melinda Czeh, Sina Stäble, Stephen Krämer, Lena Tepe, Sweta Talyan, Joana Carrelha, Yiran Meng, Barbara Heitplatz, Marius Schwabenland, Michael D. Milsom, Christoph Plass, Marco Prinz, Matthias Schlesner, Miguel A. Andrade-Navarro, Claus Nerlov, Sten Eirik W. Jacobsen, Daniel B. Lipka, Frank Rosenbauer
The Journal of Immunology January 15, 2022, 208 (2) 358-370; DOI: 10.4049/jimmunol.2100624
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