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Cell Rep. 2018 Sep 4;24(10):2784-2794. doi: 10.1016/j.celrep.2018.08.018.

Dynamics of Transcription Regulation in Human Bone Marrow Myeloid Differentiation to Mature Blood Neutrophils.

Author information

1
Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
2
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
3
Bioinformatics and Genomics Group, Centre for Genomic Regulation (CRG), Dr. Aiguader, 88, 08003 Barcelona, Spain.
4
National Center for Genomic Analysis (CNAG), Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Carrer Baldiri i Reixac 4, 08028 Barcelona, Spain.
5
Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
6
Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
7
Max Planck Institute for Molecular Genetics, Berlin, Germany.
8
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
9
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.
10
Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain; Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain; Spanish Bioinformatics Institute INB-ISCIII ES-ELIXIR, Madrid 28029, Spain.
11
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.
12
Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands. Electronic address: j.martens@ncmls.ru.nl.
13
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: t.w.kuijpers@amc.nl.

Abstract

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 overview, assessing important functional features of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of chromatin modifications, methylation, and transcriptome dynamics reveals an enforced regulation of differentiation, for cellular functions such as release of proteases, respiratory burst, cell cycle regulation, and apoptosis. We observe an early establishment of the cytotoxic capability, while the signaling components that activate these 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 chromatin landscape orchestrate the daily production of a large number of neutrophils required for innate host defense and provide a comprehensive overview of differentiating human neutrophils.

KEYWORDS:

epigenome; myeloid differentiation; neutrophil; transcriptome

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