title: The Transcriptional Repressor Polycomb Group Factor 6, PCGF6, Negatively Regulates Dendritic Cell Activation and Promotes Quiescence.
abstract: Pro-inflammatory signals provided by the microenvironment are critical to activate dendritic cells (DCs), components of the innate immune system that shape both innate and adaptive immunity. However, to prevent inappropriate immune activation, mechanisms must be in place to restrain DC activation to ensure DCs are activated only once sufficient stimuli have been received. Here, we report that DC activation and immunogenicity are regulated by the transcriptional repressor Polycomb group factor 6 (PCGF6). Pcgf6 is rapidly downregulated upon stimulation, and this downregulation is necessary to permit full DC activation. Silencing PCGF6 expression enhanced both spontaneous and stimulated DC activation. We show that PCGF6 associates with the H3K4me3 demethylase JARID1c, and together, they negatively regulate H3K4me3 levels in DCs. Our results identify two key regulators, PCGF6 and JARID1c that temper DC activation and implicate active transcriptional silencing via histone demethylation as a previously unappreciated mechanism for regulating DC activation and quiescence.
authors: Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors: Giselle M
authors: GM
authors: Boukhaled
authors: Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors: Brendan
authors: B
authors: Cordeiro
authors: The Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: Genevieve
authors: G
authors: Deblois
authors: Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors: Vassil
authors: V
authors: Dimitrov
authors: The Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: Swneke D
authors: SD
authors: Bailey
authors: Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Faculty of Biology, University of Freiburg, Freiburg, Freiburg 79104, Germany.
authors: Thomas
authors: T
authors: Holowka
authors: Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors: Anisa
authors: A
authors: Domi
authors: Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors: Hannah
authors: H
authors: Guak
authors: Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors: Huai-Hsuan Clare
authors: HH
authors: Chiu
authors: Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, the Netherlands.
authors: Bart
authors: B
authors: Everts
authors: Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Faculty of Biology, University of Freiburg, Freiburg, Freiburg 79104, Germany.
authors: Edward J
authors: EJ
authors: Pearce
authors: The Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: Mathieu
authors: M
authors: Lupien
authors: Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors: John H
authors: JH
authors: White
authors: Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada. Electronic address: connie.krawczyk@mcgill.ca.
authors: Connie M
authors: CM
authors: Krawczyk
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D056466:Histone Demethylases; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000276:immunology; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; D008070:Lipopolysaccharides; C066476:Pcgf6 protein, mouse; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D056466:Histone Demethylases; C490173:Kdm5c protein, mouse; D010089:Oxidoreductases, N-Demethylating; D063150:Polycomb Repressive Complex 1