title: Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response.
abstract: Effective antiviral immunity depends on the ability of infected cells or cells triggered with virus-derived nucleic acids to produce type I interferon (IFN), which activates transcription of numerous antiviral genes. However, disproportionately strong or chronic IFN expression is a common cause of inflammatory and autoimmune diseases. We describe an epigenetic mechanism that determines cell type-specific differences in IFN and IFN-stimulated gene (ISG) expression in response to exogenous signals. We identify di-methylation of histone H3 at lysine 9 (H3K9me2) as a suppressor of IFN and IFN-inducible antiviral gene expression. We show that levels of H3K9me2 at IFN and ISG correlate inversely with the scope and amplitude of IFN and ISG expression in fibroblasts and dendritic cells. Accordingly, genetic ablation or pharmacological inactivation of lysine methyltransferase G9a, which is essential for the generation of H3K9me2, resulted in phenotypic conversion of fibroblasts into highly potent IFN-producing cells and rendered these cells resistant to pathogenic RNA viruses. In summary, our studies implicate H3K9me2 and enzymes controlling its abundance as key regulators of innate antiviral immunity.
authors.affiliation: Laboratory of Immune Cell Epigenetics and Signaling, Rockefeller University, New York, NY 10065, USA. tfang@rockefeller.edu
authors.forename: Terry C
authors.initials: TC
authors.lastname: Fang
authors.forename: Uwe
authors.initials: U
authors.lastname: Schaefer
authors.forename: Ingrid
authors.initials: I
authors.lastname: Mecklenbrauker
authors.forename: Astrid
authors.initials: A
authors.lastname: Stienen
authors.forename: Scott
authors.initials: S
authors.lastname: Dewell
authors.forename: Marie S
authors.initials: MS
authors.lastname: Chen
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Rioja
authors.forename: Valentino
authors.initials: V
authors.lastname: Parravicini
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.forename: Rohit
authors.initials: R
authors.lastname: Chandwani
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacDonald
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Alexander
authors.initials: A
authors.lastname: Tarakhovsky
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology; D006657:Histones / Q000378:metabolism*; D007113:Immunity, Innate; D007372:Interferons / Q000096:biosynthesis*; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D014777:Virus Diseases / Q000276:immunology*
chemical_list: D006657:Histones; D007372:Interferons; D011495:Histone-Lysine N-Methyltransferase