title: IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation.
abstract: BACKGROUND
  The role of cytokines in establishing specific transcriptional programmes in innate immune cells has long been recognized. However, little is known about how these extracellular factors instruct innate immune cell epigenomes to engage specific differentiation states. Human monocytes differentiate under inflammatory conditions into effector cells with non-redundant functions, such as dendritic cells and macrophages. In this context, interleukin 4 (IL-4) and granulocyte macrophage colony-stimulating factor (GM-CSF) drive dendritic cell differentiation, whereas GM-CSF alone leads to macrophage differentiation.
  
  
  RESULTS
  Here, we investigate the role of IL-4 in directing functionally relevant dendritic-cell-specific DNA methylation changes. A comparison of DNA methylome dynamics during differentiation from human monocytes to dendritic cells and macrophages identified gene sets undergoing dendritic-cell-specific or macrophage-specific demethylation. Demethylation is TET2-dependent and is essential for acquiring proper dendritic cell and macrophage identity. Most importantly, activation of the JAK3-STAT6 pathway, downstream of IL-4, is required for the acquisition of the dendritic-cell-specific demethylation and expression signature, following STAT6 binding. A constitutively activated form of STAT6 is able to bypass IL-4 upstream signalling and instruct dendritic-cell-specific functional DNA methylation changes.
  
  
  CONCLUSIONS
  Our study is the first description of a cytokine-mediated sequence of events leading to direct gene-specific demethylation in innate immune cell differentiation.
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. rvento@idibell.cat.
authors.forename: Roser
authors.initials: R
authors.lastname: Vento-Tormo
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. carlos.company@crg.eu.|Present address: Bioinformatics Core, Centre for Genomic Regulation (CRG), 08003, Barcelona, Spain. carlos.company@crg.eu.
authors.forename: Carlos
authors.initials: C
authors.lastname: Company
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. jrubreva@idibell.cat.
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez-Ubreva
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. l.delarica@qmul.ac.uk.|Present address: Barts and The London School of Medicine and Dentistry, Centre for Neuroscience & Trauma, Blizard Institute, 4 Newark Street, London, E1 2AT, UK. l.delarica@qmul.ac.uk.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: de la Rica
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. jurquiza@creal.cat.
authors.forename: José M
authors.initials: JM
authors.lastname: Urquiza
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. biola-maria.javierre@babraham.ac.uk.|Present address: Nuclear Dynamics Programme, The Babraham Institute, Cambridge, CB22 3AT, UK. biola-maria.javierre@babraham.ac.uk.
authors.forename: Biola M
authors.initials: BM
authors.lastname: Javierre
authors.affiliation: Department of Experimental and Health Sciences, Barcelona Biomedical Research Park, Universitat Pompeu Fabra (UPF), 08003, Barcelona, Spain. sabari.radha@upf.edu.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Sabarinathan
authors.affiliation: Human Molecular Genetics Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. aluque@idibell.cat.
authors.forename: Ana
authors.initials: A
authors.lastname: Luque
authors.affiliation: Cancer Epigenetics Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. mesteller@idibell.cat.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Human Molecular Genetics Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. jaran@idibell.cat.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Aran
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. dalvarez@idibell.cat.
authors.forename: Damiana
authors.initials: D
authors.lastname: Álvarez-Errico
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. eballestar@idibell.cat.
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology; D049308:Dioxygenases; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C508598:IL4 protein, human; D011518:Proto-Oncogene Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4; D016173:Macrophage Colony-Stimulating Factor; D049308:Dioxygenases; C541081:TET2 protein, human