Contributors: Régulation épigénétique - Epigenetic regulation; Institut Pasteur Paris -Centre National de la Recherche Scientifique (CNRS); Institut Pasteur Paris; Biophysique des macromolécules et leurs interactions; Aarhus University Aarhus; Aarhus University Hospital; This work was supported in part by the Agence National pour la Recherche, by the Fondation pour la Recherche Medicale, and by the ARSEP foundation. PS received support from the Sandwich Fellowship Program of the French Embassy in India and from the Institut National de la Santé et de la Recherche Médicale. TC, AM-L, and TP were supported by the Aase and Ejnar Danielsen Foundation and the Danish MS Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank P. R. Thompson for the gift of Cl-amidine; A. A. Cook, T. Kouzarides, and M. Yamada for PADI4 cDNAs; the Department of Neurology, Aarhus University Hospital, Denmark, for mediating the blood samples; E. Allemand, B. Baron, and M. Vera Ugalde for technical advice and valuable discussion; and J. Seeler and A. Kumar for critical reading of the manuscript.
نبذة مختصرة : International audience ; Multiple Sclerosis (MS) is an autoimmune disease associated with abnormal expression of a subset of cytokines, resulting in inappropriate T-lymphocyte activation and uncontrolled immune response. A key issue in the field is the need to understand why these cytokines are transcriptionally activated in the patients. Here, we have examined several transcription units subject to pathological reactivation in MS, including the TNFa and IL8 cytokine genes and also several Human Endogenous RetroViruses (HERVs). We find that both the immune genes and the HERVs require the heterochromatin protein HP1a for their transcriptional repression. We further show that the Peptidylarginine Deiminase 4 (PADI4), an enzyme with a suspected role in MS, weakens the binding of HP1a to tri-methylated histone H3 lysine 9 by citrullinating histone H3 arginine 8. The resulting de-repression of both cytokines and HERVs can be reversed with the PADI-inhibitor Cl-amidine. Finally, we show that in peripheral blood mononuclear cells (PBMCs) from MS patients, the promoters of TNFa, and several HERVs share a deficit in HP1a recruitment and an augmented accumulation of histone H3 with a double citrulline 8 trimethyl lysine 9 modifications. Thus, our study provides compelling evidence that HP1a and PADI4 are regulators of both immune genes and HERVs, and that multiple events of transcriptional reactivation in MS patients can be explained by the deficiency of a single mechanism of gene silencing.
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