Cell Reports (Sep 2018)
Dynamics of Transcription Regulation in 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 T.J. 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 H.A. Martens,
- Taco W. Kuijpers
Affiliations
- Luigi Grassi
- Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
- Farzin Pourfarzad
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Sebastian Ullrich
- Bioinformatics and Genomics Group, Centre for Genomic Regulation (CRG), Dr. Aiguader, 88, 08003 Barcelona, Spain
- Angelika Merkel
- 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
- Felipe Were
- Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain
- Enrique Carrillo-de-Santa-Pau
- Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain
- Guoqiang Yi
- Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
- Ida H. Hiemstra
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Anton T.J. Tool
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Erik Mul
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Juliane Perner
- Max Planck Institute for Molecular Genetics, Berlin, Germany
- Eva Janssen-Megens
- Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
- Kim Berentsen
- Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
- Hinri Kerstens
- Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
- Ehsan Habibi
- Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
- Marta Gut
- 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
- Marie Laure Yaspo
- Max Planck Institute for Molecular Genetics, Berlin, Germany
- Matthias Linser
- Max Planck Institute for Molecular Genetics, Berlin, Germany
- Ernesto Lowy
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
- Avik Datta
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
- Laura Clarke
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
- Paul Flicek
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
- Martin Vingron
- Max Planck Institute for Molecular Genetics, Berlin, Germany
- Dirk Roos
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Timo K. van den Berg
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Simon Heath
- 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
- Daniel Rico
- Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain
- Mattia Frontini
- 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
- Myrto Kostadima
- Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
- Ivo Gut
- 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
- Alfonso Valencia
- 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
- Willem H. Ouwehand
- 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
- Hendrik G. Stunnenberg
- Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
- Joost H.A. Martens
- Radboud University, Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands; Corresponding author
- Taco W. Kuijpers
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Corresponding author
- Journal volume & issue
-
Vol. 24,
no. 10
pp. 2784 – 2794
Abstract
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 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. : Grassi et al. report that the establishment of transcriptional enhancers drives neutrophil differentiation. Coordinated waves of gene expression establish the cytotoxic capability of these cells at early stages of maturation. A set of super-enhancers is specifically opened at the end of the differentiation process to control neutrophil activation. Keywords: neutrophil, epigenome, transcriptome, myeloid differentiation
