The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-γ locus

Cell. 2013 Feb 14;152(4):743-54. doi: 10.1016/j.cell.2013.01.015.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Cardiovirus Infections / immunology
  • Disease Susceptibility*
  • Epigenesis, Genetic*
  • Interferon-gamma / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • RNA, Long Noncoding / genetics*
  • Salmonella Infections / immunology
  • Salmonella typhimurium / immunology
  • Theilovirus / immunology

Substances

  • RNA, Long Noncoding
  • Interferon-gamma