Conserved RNA structural elements mediate WDR5 recognition of the long non-coding RNA UMLILO

The long non-coding RNA (lncRNA), UMLILO (upstream master lncRNA of the inflammatory chemokine locus), regulates the epigenetic programming of innate immune genes. Although its basic mechanism was revealed in cells, the molecular basis by which UMLILO interacts with its partner, WD repeat-containing protein 5 (WDR5), remained unknown. To understand how UMLILO interacts with WDR5, we determined the secondary structure of UMLILO by chemical probing and performed binding assays, uncovering the multivalent nature of their interaction, involving multiple RNA stem-loops. Conservational analysis revealed a stem-loop structurally conserved across mammals. Furthermore, we found that UMLILO engages multiple sites on the surface of WDR5 as revealed by NMR chemical shift perturbation analysis, and that full-length UMLILO increases WDR5 recruitment into in vitro condensates. Our report provides a detailed characterization of the molecular basis of WDR5 recognition by an RNA and establishes a new paradigm for the role of IPLs in enhancing gene expression.