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

Maximilian Schönung, Mark Hartmann, Stephen Krämer, Sina Stäble, Mariam Hakobyan, Emely Kleinert, Theo Aurich, Defne Cobanoglu, Florian H. Heidel, Stefan Fröhling, Michael D. Milsom, Matthias Schlesner, Pavlo Lutsik, Daniel B. Lipka
doi: https://doi.org/10.1101/2022.06.02.493896
Maximilian Schönung
1Section Translational Cancer Epigenomics, Division Translational Medical Oncology, German Cancer Research Center (DKFZ) & National Center for Tumor Diseases (NCT), Heidelberg, Germany
2Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
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Mark Hartmann
1Section Translational Cancer Epigenomics, Division Translational Medical Oncology, German Cancer Research Center (DKFZ) & National Center for Tumor Diseases (NCT), Heidelberg, Germany
3Division 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
1Section Translational Cancer Epigenomics, Division Translational Medical Oncology, German Cancer Research Center (DKFZ) & National Center for Tumor Diseases (NCT), Heidelberg, Germany
2Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
4Biomedical 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
1Section Translational Cancer Epigenomics, Division Translational Medical Oncology, German Cancer Research Center (DKFZ) & National Center for Tumor Diseases (NCT), Heidelberg, Germany
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Mariam Hakobyan
1Section Translational Cancer Epigenomics, Division Translational Medical Oncology, German Cancer Research Center (DKFZ) & National Center for Tumor Diseases (NCT), Heidelberg, Germany
2Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
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Emely Kleinert
1Section Translational Cancer Epigenomics, Division Translational Medical Oncology, German Cancer Research Center (DKFZ) & National Center for Tumor Diseases (NCT), Heidelberg, Germany
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Theo Aurich
5Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg, Germany
6Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
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Defne Cobanoglu
1Section Translational Cancer Epigenomics, Division Translational Medical Oncology, German Cancer Research Center (DKFZ) & National Center for Tumor Diseases (NCT), Heidelberg, Germany
7Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
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Florian H. Heidel
8Innere Medizin C, Universitätsmedizin Greifswald, Greifswald, Germany
9Leibniz Institute on Aging, Fritz-Lipmann-Institute, Jena, Germany
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Stefan Fröhling
10Division Translational Medical Oncology, German Cancer Research Center (DKFZ) & National Center for Tumor Diseases (NCT), Heidelberg, Germany
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Michael D. Milsom
5Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg, Germany
6Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
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Matthias Schlesner
4Biomedical 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
11Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Daniel B. Lipka
1Section Translational Cancer Epigenomics, Division Translational Medical Oncology, German Cancer Research Center (DKFZ) & National Center for Tumor Diseases (NCT), Heidelberg, Germany
12Faculty of Medicine, Otto-von-Guericke-University, Magdeburg, Germany
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  • For correspondence: d.lipka@dkfz.de
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ABSTRACT

Background The differentiation of hematopoietic stem and progenitor cells (HSPCs) to terminally differentiated immune cells is accompanied by large-scale remodeling of the DNA methylation landscape. While significant insights into the molecular mechanisms of hematopoietic tissue regeneration were derived from mouse models, profiling of DNA methylation changes has been hampered by high cost or low resolution using the methods available. This problem has been overcome by the recent development of the Infinium Mouse Methylation BeadChip (MMBC) array, facilitating methylation profiling of the mouse genome at single CpG resolution at affordable cost.

Results We extended the RnBeads package to provide a computational framework for the analysis of MMBC data. This framework was applied to a newly generated MMBC reference map of mouse hematopoiesis encompassing nine different cell types. The analysis of dynamically regulated CpG sites showed progressive and unidirectional DNA methylation changes from HSPCs to differentiated hematopoietic cells and allowed the identification of lineage- and cell type-specific DNA methylation programs. Comparison to previously published catalogues of cis-regulatory elements (CREs) revealed 12,856 novel putative CREs which 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.

Conclusions We established a publicly available analysis pipeline for MMBC datasets 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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 03, 2022.
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Dynamic DNA methylation reveals novel cis-regulatory elements in murine hematopoiesis
Maximilian Schönung, Mark Hartmann, Stephen Krämer, Sina Stäble, Mariam Hakobyan, Emely Kleinert, Theo Aurich, Defne Cobanoglu, Florian H. Heidel, Stefan Fröhling, Michael D. Milsom, Matthias Schlesner, Pavlo Lutsik, Daniel B. Lipka
bioRxiv 2022.06.02.493896; doi: https://doi.org/10.1101/2022.06.02.493896
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Dynamic DNA methylation reveals novel cis-regulatory elements in murine hematopoiesis
Maximilian Schönung, Mark Hartmann, Stephen Krämer, Sina Stäble, Mariam Hakobyan, Emely Kleinert, Theo Aurich, Defne Cobanoglu, Florian H. Heidel, Stefan Fröhling, Michael D. Milsom, Matthias Schlesner, Pavlo Lutsik, Daniel B. Lipka
bioRxiv 2022.06.02.493896; doi: https://doi.org/10.1101/2022.06.02.493896

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