title: Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.
abstract: Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naïve, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. β-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans.
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Sadia
authors.initials: S
authors.lastname: Saeed
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Quintin
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Hindrik H D
authors.initials: HH
authors.lastname: Kerstens
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Nagesha A
authors.initials: NA
authors.lastname: Rao
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Ali
authors.initials: A
authors.lastname: Aghajanirefah
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Filomena
authors.initials: F
authors.lastname: Matarese
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Shih-Chin
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ratter
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Berentsen
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Martijn A
authors.initials: MA
authors.lastname: van der Ent
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Nilofar
authors.initials: N
authors.lastname: Sharifi
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Janssen-Megens
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: Ter Huurne
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Amit
authors.initials: A
authors.lastname: Mandoli
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van Schaik
authors.affiliation: Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA 02114, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Aylwin
authors.initials: A
authors.lastname: Ng
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, UK. National Health Service, Blood and Transplant Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB0 2PT, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Burden
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, UK. National Health Service, Blood and Transplant Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB0 2PT, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, UK. National Health Service, Blood and Transplant Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB0 2PT, UK.
authors.forename: Mattia
authors.initials: M
authors.lastname: Frontini
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Fourth Department of Internal Medicine, University of Athens, Medical School, 1 Rimini Street, 12462 Athens, Greece.
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, UK. National Health Service, Blood and Transplant Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB0 2PT, UK.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Joost H A
authors.initials: JH
authors.lastname: Martens
authors.affiliation: Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA 02114, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands. h.stunnenberg@ncmls.ru.nl mihai.netea@radboudumc.nl c.logie@ncmls.ru.nl.
authors.forename: Colin
authors.initials: C
authors.lastname: Logie
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. h.stunnenberg@ncmls.ru.nl mihai.netea@radboudumc.nl c.logie@ncmls.ru.nl.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands. h.stunnenberg@ncmls.ru.nl mihai.netea@radboudumc.nl c.logie@ncmls.ru.nl.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D003850:Deoxyribonuclease I / Q000737:chemistry; D044127:Epigenesis, Genetic; D018392:Genomic Imprinting; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007156:Immunologic Memory; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000166:cytology* / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism; D047071:beta-Glucans / Q000276:immunology
chemical_list: D058847:Inflammasomes; D014157:Transcription Factors; D047071:beta-Glucans; D003850:Deoxyribonuclease I