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T helper 17 (TH17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORγt, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a RORγt partner that coordinates transcription of selective TH17 genes, and is required for TH17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORγt 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-RORγt interaction and RORγt target gene transcription. Elucidation of the link between Rmrp and the DDX5-RORγt complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in TH17-dependent diseases.

Original publication

DOI

10.1038/nature16193

Type

Journal article

Journal

Nature

Publication Date

24/12/2015

Volume

528

Pages

517 - 522

Keywords

Animals, Chromatin, DEAD-box RNA Helicases, Female, Gene Expression Regulation, Hair, Hirschsprung Disease, Humans, Immunologic Deficiency Syndromes, Inflammation, Male, Mice, Mice, Inbred C57BL, Mutation, Nuclear Receptor Subfamily 1, Group F, Member 3, Organ Specificity, Osteochondrodysplasias, Protein Binding, RNA, Long Noncoding, Th17 Cells, Transcription, Genetic