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

Long noncoding RNAs (IncRNAs) are increasingly appreciated as regulators of cell-specific gene expression. Here, an enhancer-like IncRNA 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 IncRNA expression, increased interferon-gamma (IFN-gamma) abundance in activated CD8(+) T cells, increased Theiler's virus persistence, and decreased Salmonella enterica pathogenesis. Transgenic expression of NeST IncRNA 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-gamma locus. Thus, this IncRNA regulates epigenetic marking of IFN-gamma-encoding chromatin, expression of IFN-gamma, and susceptibility to a viral and a bacterial pathogen.