Exploring the role of a novel autoimmune disease-associated lncRNA in Treg biology

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PROJECT SUMMARY/ABSTRACT Long non-coding RNAs (lncRNAs) are now established as important regulators of diverse biological processes. Tens of thousands of non-coding transcripts have been detected by RNA sequencing, yet only a minute fraction of these have been functionally characterized. LncRNAs are of potential clinical significance, as they are increasingly considered as targets for the development of novel therapeutic approaches. We have established a systematic approach to specifically identify lncRNAs that are likely to be functional regulators of the immune system and that may be involved in inflammatory and autoimmune diseases. This discovery pipeline integrates information from genome-wide association studies (GWAS), evolutionary conservation between mice and humans, and differential expression patterns in immune cells. Using this approach, we have identified a previously unknown human lncRNA, which we have named lnc15. Lnc15 is present in mice and humans, and overlaps with a single-nucleotide polymorphism that has been linked to Crohn’s disease and ulcerative colitis, two severe intestinal auto-immune pathologies. Importantly, we have found that lnc15 is present at high levels in regulatory T cells (Tregs) but only at low levels in other T-cell subsets. We have generated lnc15 knockout mice and, intriguingly, have observed that these animals exhibit exacerbated disease progression in a model of intestinal inflammation. Additionally, Tregs isolated from lnc15-deficient mice are less effective at suppressing the proliferation of naive T cells, whereas overexpression of lnc15 enhances expression of IL-10, an important effector cytokine of Tregs. Based on these observations, we hypothesize that lnc15 is a novel regulator of Treg function. The experiments proposed here will explore this hypothesis by determining how lnc15 affects the Treg transcriptome and identifying its protein and chromatin interaction partners. To evaluate the physiological relevance of lnc15 in vivo, we further propose to utilize Treg-specific models of intestinal inflammation and determine the effect of lnc15 deficiency on T-cell development, differentiation and homeostasis.