The Transcriptional Repressor Polycomb Group Factor 6, PCGF6, Negatively Regulates Dendritic Cell Activation and Promotes Quiescence
Giselle M. Boukhaled,
Brendan Cordeiro,
Genevieve Deblois,
Vassil Dimitrov,
Swneke D. Bailey,
Thomas Holowka,
Anisa Domi,
Hannah Guak,
Huai-Hsuan Clare Chiu,
Bart Everts,
Edward J. Pearce,
Mathieu Lupien,
John H. White,
Connie M. Krawczyk
Affiliations
Giselle M. Boukhaled
Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada
Brendan Cordeiro
Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada
Genevieve Deblois
The Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
Vassil Dimitrov
Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada
Swneke D. Bailey
The Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
Thomas Holowka
Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Faculty of Biology, University of Freiburg, Freiburg, Freiburg 79104, Germany
Anisa Domi
Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada
Hannah Guak
Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada
Huai-Hsuan Clare Chiu
Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada
Bart Everts
Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, the Netherlands
Edward J. Pearce
Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Faculty of Biology, University of Freiburg, Freiburg, Freiburg 79104, Germany
Mathieu Lupien
The Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
John H. White
Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada
Connie M. Krawczyk
Goodman Cancer Research Center, Departments of Microbiology and Immunology and Physiology, McGill University, Montreal, QC H3G 1Y6, Canada
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.
