The NeST Long ncRNA Controls Microbial Susceptibility and Epigenetic Activation of the Interferon-γ Locus

• Published in: Cell 2013-02, Vol.152 (4), p.743-754
• Main Authors: Gomez, J. Antonio, Wapinski, Orly L., Yang, Yul W., Bureau, Jean-François, Gopinath, Smita, Monack, Denise M., Chang, Howard Y., Brahic, Michel, Kirkegaard, Karla
• Format: Article
• Language: English
• Subjects: Animals; Cardiovirus Infections - immunology; CD8-positive T-lymphocytes; CD8-Positive T-Lymphocytes - immunology; chromatin; crossing; Disease Susceptibility; Epigenesis, Genetic; epigenetics; gene expression; genes; histones; interferon-gamma; Interferon-gamma - genetics; loci; lysine; methylation; methyltransferases; Mice; Mice, Inbred C57BL; Mice, Transgenic; non-coding RNA; pathogenesis; pathogens; phenotype; RNA, Long Noncoding - genetics; Salmonella; Salmonella enterica; Salmonella Infections - immunology; Salmonella typhimurium - immunology; Theilovirus - immunology; viruses
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.01.015

Long noncoding RNAs (lncRNAs) are increasingly appreciated as regulators of cell-specific gene expression. Here, an enhancer-like lncRNA termed NeST (nettoie Salmonella pas Theiler’s [cleanup Salmonella not Theiler’s]) is shown to be causal for all phenotypes conferred by murine viral susceptibility locus Tmevp3. This locus was defined by crosses between SJL/J and B10.S mice and contains several candidate genes, including NeST. The SJL/J-derived locus confers higher lncRNA expression, increased interferon-γ (IFN-γ) abundance in activated CD8+ T cells, increased Theiler’s virus persistence, and decreased Salmonella enterica pathogenesis. Transgenic expression of NeST lncRNA alone was sufficient to confer all phenotypes of the SJL/J locus. NeST RNA was found to bind WDR5, a component of the histone H3 lysine 4 methyltransferase complex, and to alter histone 3 methylation at the IFN-γ locus. Thus, this lncRNA regulates epigenetic marking of IFN-γ-encoding chromatin, expression of IFN-γ, and susceptibility to a viral and a bacterial pathogen. [Display omitted] ► Dissection of viral susceptibility locus reveals the role of a long noncoding RNA, NeST ► NeST RNA expression is required for inducible IFN-γ synthesis in CD8+ T cells ► NeST RNA increases Theiler’s virus persistence and reduces Salmonella lethality ► NeST binds to histone modification complex, changing epigenetic marks at the Ifng locus NeST, a long noncoding RNA whose expression and sequence are polymorphic in murine and human populations, epigenetically controls the expression of interferon-γ and confers differential pathogen susceptibility in the mouse.