Group 1 innate lymphoid cell lineage identity is determined by a cis-regulatory element marked by a long non-coding RNA

© 2017 Elsevier Inc.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. We identified a cis-regulatory element demarcated by a long non-coding RNA (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. Thus, 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.The work in this manuscript was supported by funds from CHOP, UPenn IFI and IDOM pilot projects, the PEW Foundation, and NIH R21AI128060, R21DK111755, and R01HL136572 (J.H.-M.). A.W. and R.A.F. were supported by NIH R21AI110776; R.A.F. by the Howard Hughes Medical Institute; I.E.B. by NIH R01AI103062 and R01AI128530; W.K.M. by NIH T32AI055428 and F31AI124538; J.J.K. by NIH T32DK007780; S.P.S. by NIH F30DK094708; and A.R. and M.C.D. by New Innovator NIH DP2OD008514, NIH R33EB019767, and NSF CAREER 1350601. E.J.W. is a member of the Parker Institute for Cancer Immunotherapy, which supports the Penn Cancer Immunotherapy Program. H.V.-F. is funded by ERC (647274), EU; Kenneth Rainin Foundation, US; Crohn’s and Colitis Foundation of America, US; and FCT, Portugal. A.R. receives royalty and consulting income related to Stellaris RNA FISH probes from LGC/Biosearch Technologies.