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Epigenomic and functional dynamics of human bone marrow myeloid differentiation to mature blood neutrophils

View ORCID ProfileLuigi Grassi, Farzin Pourfarzad, Sebastian Ullrich, View ORCID ProfileAngelika Merkel, Felipe Were, Enrique Carrillo de Santa Pau, Guoqiang Yi, Ida H Hiemstra, Anton TJ Tool, Erik Mul, Juliane Perner, Eva Janssen-Megens, Kim Berentsen, Hinri Kerstens, Ehsan Habibi, Marta Gut, Marie Laure Yaspo, Matthias Linser, Ernesto Lowy, Avik Datta, Laura Clarke, Paul Flicek, Martin Vingron, Dirk Roos, Timo K van den Berg, Simon Heath, Daniel Rico, Mattia Frontini, Myrto Kostadima, Ivo Gut, Alfonso Valencia, Willem H Ouwehand, View ORCID ProfileHendrik G Stunnenberg, Joost HA Martens, View ORCID ProfileTaco W Kuijpers
doi: https://doi.org/10.1101/295014
Luigi Grassi
1Department of Haematology, University of Cambridge, Cambridge CB2 0PT, United Kingdom.
2National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 OPT, United Kingdom.
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Farzin Pourfarzad
3Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Sebastian Ullrich
4Bioinformatics and Genomics Group, Centre for Genomic Regulation (CRG), Dr. Aiguader, 88, 08003 Barcelona, Spain.
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Angelika Merkel
5National Center for Genomic Analysis (CNAG), Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Carrer Baldiri i Reixac 4, 08028 Barcelona, Spain.
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Felipe Were
6Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
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Enrique Carrillo de Santa Pau
6Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
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Guoqiang Yi
7Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
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Ida H Hiemstra
3Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Anton TJ Tool
3Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Erik Mul
3Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Juliane Perner
8Max Planck Institute for Molecular Genetics, Berlin, Germany.
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Eva Janssen-Megens
7Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
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Kim Berentsen
7Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
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Hinri Kerstens
7Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
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Ehsan Habibi
7Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
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Marta Gut
5National Center for Genomic Analysis (CNAG), Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Carrer Baldiri i Reixac 4, 08028 Barcelona, Spain.
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Marie Laure Yaspo
8Max Planck Institute for Molecular Genetics, Berlin, Germany.
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Matthias Linser
8Max Planck Institute for Molecular Genetics, Berlin, Germany.
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Ernesto Lowy
9European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
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Avik Datta
9European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
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Laura Clarke
9European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
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Paul Flicek
9European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
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Martin Vingron
8Max Planck Institute for Molecular Genetics, Berlin, Germany.
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Dirk Roos
3Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Timo K van den Berg
3Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Simon Heath
5National Center for Genomic Analysis (CNAG), Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Carrer Baldiri i Reixac 4, 08028 Barcelona, Spain.
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Daniel Rico
6Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
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Mattia Frontini
1Department of Haematology, University of Cambridge, Cambridge CB2 0PT, United Kingdom.
2National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 OPT, United Kingdom.
10British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0QQ, United Kingdom.
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Myrto Kostadima
1Department of Haematology, University of Cambridge, Cambridge CB2 0PT, United Kingdom.
2National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 OPT, United Kingdom.
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Ivo Gut
5National Center for Genomic Analysis (CNAG), Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Carrer Baldiri i Reixac 4, 08028 Barcelona, Spain.
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Alfonso Valencia
6Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
11Spanish Bioinformatics Institute INB-ISCIII ES-ELIXIR.
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Willem H Ouwehand
1Department of Haematology, University of Cambridge, Cambridge CB2 0PT, United Kingdom.
2National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 OPT, United Kingdom.
10British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0QQ, United Kingdom.
12Department of Human Genetics, the Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, United Kingdom.
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Hendrik G Stunnenberg
7Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
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Joost HA Martens
7Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
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  • For correspondence: J.Martens@ncmls.ru.nl t.w.kuijpers@amc.nl
Taco W Kuijpers
3Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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  • For correspondence: J.Martens@ncmls.ru.nl t.w.kuijpers@amc.nl
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Summary

Neutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic and functional overview of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of epigenetic and transcriptome dynamics reveals an enforced regulation of differentiation, through cellular functions such as: release of proteases, respiratory burst, cell cycle regulation and apoptosis. We observe an early establishment of the cytotoxic capability, whilst the signaling components that activate antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the epigenetic landscape orchestrate the daily production of large number of neutrophils required for innate host defense and provide a comprehensive overview of the epigenomes of differentiating human neutrophils.

Key points

  • Dynamic acetylation enforces human neutrophil progenitor differentiation.

  • Neutrophils cytotoxic capability is established early at the (pro)myelocyte stage.

  • Coordinated signaling component expression prevents unwanted toxic effects to the bone marrow niche.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 05, 2018.
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Epigenomic and functional dynamics of human bone marrow myeloid differentiation to mature blood neutrophils
Luigi Grassi, Farzin Pourfarzad, Sebastian Ullrich, Angelika Merkel, Felipe Were, Enrique Carrillo de Santa Pau, Guoqiang Yi, Ida H Hiemstra, Anton TJ Tool, Erik Mul, Juliane Perner, Eva Janssen-Megens, Kim Berentsen, Hinri Kerstens, Ehsan Habibi, Marta Gut, Marie Laure Yaspo, Matthias Linser, Ernesto Lowy, Avik Datta, Laura Clarke, Paul Flicek, Martin Vingron, Dirk Roos, Timo K van den Berg, Simon Heath, Daniel Rico, Mattia Frontini, Myrto Kostadima, Ivo Gut, Alfonso Valencia, Willem H Ouwehand, Hendrik G Stunnenberg, Joost HA Martens, Taco W Kuijpers
bioRxiv 295014; doi: https://doi.org/10.1101/295014
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Epigenomic and functional dynamics of human bone marrow myeloid differentiation to mature blood neutrophils
Luigi Grassi, Farzin Pourfarzad, Sebastian Ullrich, Angelika Merkel, Felipe Were, Enrique Carrillo de Santa Pau, Guoqiang Yi, Ida H Hiemstra, Anton TJ Tool, Erik Mul, Juliane Perner, Eva Janssen-Megens, Kim Berentsen, Hinri Kerstens, Ehsan Habibi, Marta Gut, Marie Laure Yaspo, Matthias Linser, Ernesto Lowy, Avik Datta, Laura Clarke, Paul Flicek, Martin Vingron, Dirk Roos, Timo K van den Berg, Simon Heath, Daniel Rico, Mattia Frontini, Myrto Kostadima, Ivo Gut, Alfonso Valencia, Willem H Ouwehand, Hendrik G Stunnenberg, Joost HA Martens, Taco W Kuijpers
bioRxiv 295014; doi: https://doi.org/10.1101/295014

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