title: Extensive remodeling of DC function by rapid maturation-induced transcriptional silencing.
abstract: The activation, or maturation, of dendritic cells (DCs) is crucial for the initiation of adaptive T-cell mediated immune responses. Research on the molecular mechanisms implicated in DC maturation has focused primarily on inducible gene-expression events promoting the acquisition of new functions, such as cytokine production and enhanced T-cell-stimulatory capacity. In contrast, mechanisms that modulate DC function by inducing widespread gene-silencing remain poorly understood. Yet the termination of key functions is known to be critical for the function of activated DCs. Genome-wide analysis of activation-induced histone deacetylation, combined with genome-wide quantification of activation-induced silencing of nascent transcription, led us to identify a novel inducible transcriptional-repression pathway that makes major contributions to the DC-maturation process. This silencing response is a rapid primary event distinct from repression mechanisms known to operate at later stages of DC maturation. The repressed genes function in pivotal processes--including antigen-presentation, extracellular signal detection, intracellular signal transduction and lipid-mediator biosynthesis--underscoring the central contribution of the silencing mechanism to rapid reshaping of DC function. Interestingly, promoters of the repressed genes exhibit a surprisingly high frequency of PU.1-occupied sites, suggesting a novel role for this lineage-specific transcription factor in marking genes poised for inducible repression.
authors.affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.
authors.forename: Queralt
authors.initials: Q
authors.lastname: Seguín-Estévez
authors.affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dunand-Sauthier
authors.affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lemeille
authors.affiliation: Vital-IT, Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Iseli
authors.affiliation: Vital-IT, Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Ibberson
authors.affiliation: Vital-IT, Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Ioannidis
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland University of Basel, CH-4051 Basel, Switzerland.
authors.forename: Christoph D
authors.initials: CD
authors.lastname: Schmid
authors.affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousseau
authors.affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.
authors.forename: Emmanuèle
authors.initials: E
authors.lastname: Barras
authors.affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.
authors.forename: Antoine
authors.initials: A
authors.lastname: Geinoz
authors.affiliation: Vital-IT, Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.affiliation: Department of Biochemistry, Faculty of Biology and Medicine, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Acha-Orbea
authors.affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland walter.reith@unige.ch.
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C083728:MHC class II transactivator protein
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