Journal
NATURE
Volume 528, Issue 7583, Pages 517-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature16193
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Funding
- Cancer Research Institute Irvington Postdoctoral Fellowship
- Institutional NRSA [T32 CA009161_Levy]
- National Multiple Sclerosis Society postdoctoral fellowship [FG 2089-A-1]
- Crohn's and Colitis Foundation of America [329388]
- Dale and Betty Frey Fellowship of the Damon Runyon Cancer Research Foundation [2105-12]
- HHMI Exceptional Research Opportunities Program
- NIH [F30 1F30CA189514-01, P50-HG007735, R01HG004361, R01AI080885, R01DK103358]
- Howard Hughes Medical Institute
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T helper 17 (T(H)17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by ROR gamma t, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a ROR gamma t partner that coordinates transcription of selective T(H)17 genes, and is required for T(H)17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with ROR gamma t and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5-ROR gamma t interaction and ROR gamma t target gene transcription. Elucidation of the link between Rmrp and the DDX5-ROR gamma t complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in T(H)17-dependent diseases.
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