Long noncoding RNA (lncRNA) is a recently discovered class of intergenic regulatory elements. In Cell, Gomez et al. report the functional activity of NeST, an enhancer-like lncRNA associated with interferon-γ (IFN-γ) expression. NeST is encoded by a conserved gene adjacent to the Ifng locus; however, polymorphisms exist in mice that alter its expression, a trait that confers susceptibility to Theiler's virus but resistance to Salmonella infection. CD4+ T cells and natural killer cells have low expression of NeST, but activated CD8+ T cells have higher expression of NeST. The lncRNA can function in either cis or trans to promote Ifng expression. NeST associates with WDR5, a component of the histone 3 lysine 4–methyltransferase complex that modifies the Ifng regulatory loci. NeST expression correlates with a greater abundance of trimethylated histone 3 lysine 4. Hence, NeST confers target specificity for epigenetic modification. It is unclear whether Ifng is the only target of NeST lncRNA; however, other examples of lncRNA-mediated gene regulation are sure to come.

Cell 152, 743–754 (2013)