BPS2026 – Characterization of an immune gene priming lncRNA and its interaction with WDR5

The molecular mechanisms underlying trained immunity are poorly understood, but increasing evidence implicates long non-coding RNAs (lncRNAs) in its regulation. The upstream master LncRNA of the inflammatory chemokine locus (UMLILO) has been shown to regulate epigenetic priming of chemokine genes through interactions with the WD repeat-containing protein 5 (WDR5)-mixed lineage leukemia protein 1 (MLL1) complex. Exposure of monocytes to β-glucan stimulates increased transcription of UMLILO, which is transcribed near the promoters of chemokine genes. UMLILO recruits the MLL1/WDR5 complex to these gene promoters, where the methylation complex marks the genes for downstream transcriptional activation in response to future stimuli. In this work, we have investigated the structural mechanism by which WDR5 brings these components together using bioinformatics, chemical probing experiments, and in vitro binding assays. Our work reveals that UMLILO adopts a secondary structure that is conserved across divergent species, that WDR5 binds with nanomolar affinity to UMLILO and interacts with multiple hairpins, and that WDR5 binds each hairpin with nanomolar affinity. This provides insight into how UMLILIO interacts with WDR5 to exert transcriptional control and serves the overall goal of enhancing our understanding of how lncRNAs regulate gene expression in cells.