title: Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types.
abstract: A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability.
  
  
  
  We apply a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14+CD16-monocytes, CD66b+CD16+neutrophils, and CD4+CD45RA+naïve T cells from the same 125 healthy individuals. We discover substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression are found to be implicated in key immune pathways and are associated with cellular properties and environmental exposure. We also observe increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites are enriched at dynamic chromatin regions and active enhancers.
  
  
  
  Our data highlight the importance of transcriptional and epigenetic variability for the key role of neutrophils as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from: http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability .
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain. s.ecker@ucl.ac.uk.|UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK. s.ecker@ucl.ac.uk.
authors.forename: Simone
authors.identifier: 0000-0001-5648-1710
authors.initials: S
authors.lastname: Ecker
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.|Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, Hinxton, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: Vera
authors.initials: V
authors.lastname: Pancaldi
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, Hinxton, UK.|National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.|European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
authors.forename: Frederik O
authors.initials: FO
authors.lastname: Bagger
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Fernández
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Carrillo de Santa Pau
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Juan
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Mann
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Watt
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Casale
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.|Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.|The Bioinformatics Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.
authors.forename: Nikos
authors.initials: N
authors.lastname: Sidiropoulos
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.|Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.|The Bioinformatics Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Rapin
authors.affiliation: 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.
authors.forename: Angelika
authors.initials: A
authors.lastname: Merkel
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, 6525GA, The Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stegle
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, Hinxton, UK.|National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.|British Heart Foundation Centre of Excellence, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
authors.forename: Mattia
authors.initials: M
authors.lastname: Frontini
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, Hinxton, UK.|National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.affiliation: Department of Human Genetics, McGill University, 740 Dr. Penfield, Montreal, H3A 0G1, Canada.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Plesmanlaan 125, Amsterdam, 1066CX, The Netherlands.|Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Location H7-230, Meibergdreef 9, Amsterdam, 1105AX, The Netherlands.
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.|Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rico
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK. ns6@sanger.ac.uk.|Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, Hinxton, UK. ns6@sanger.ac.uk.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK. dsp35@medschl.cam.ac.uk.|Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge, CB1 8RN, UK. dsp35@medschl.cam.ac.uk.
authors.forename: Dirk S
authors.identifier: 0000-0002-8230-0116
authors.initials: DS
authors.lastname: Paul
mesh_terms: D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007107:Immune System / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D012737:Sex Factors; D014158:Transcription, Genetic
keywords: DNA methylation; Differential variability; Gene expression; Heterogeneity; Immune cells; Monocytes; Neutrophils; Phenotypic plasticity; T cells