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.