Epigenetic Control of Innate Lymphoid Cell Homeostasis and Development

Commitment to the innate lymphoid cell (ILC) lineage is determined by Id2, a transcriptional regulator that antagonizes T and B cell-specific gene expression programs. Yet how Id2 expression is regulated in each ILC subset remains poorly understood. Emerging data suggests that epigenetic regulation by long non-coding RNAs (lncRNAs) plays a critical role in cell type-specific regulation of gene expression in immune cells. In this thesis, we identified a cis-regulatory element demarcated by a lncRNA that controls the function and lineage identity of group 1 ILCs, while being dispensable for early ILC development and homeostasis of ILC2s and ILC3s. The locus encoding this lncRNA, which we termed Rroid, directly interacted with the promoter of its neighboring gene, Id2, in group 1 ILCs. Moreover, the Rroid locus, but not the lncRNA itself, controlled the identity and function of ILC1s by promoting chromatin accessibility and deposition of STAT5 at the promoter of Id2 in response to interleukin (IL)-15. Furthermore, a second regulatory element, which we called Id2-DS3, regulated ILC2 levels by promoting their early development. Thus, this study suggests that non-coding elements responsive to extracellular cues unique to each ILC subset represent a key regulatory layer for controlling the identity and function of ILCs