title: DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions.
abstract: 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.
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Huang
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Thomas
authors.affiliation: Center for Personal Dynamic Regulomes, Stanford University, Stanford, California 94305, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Flynn
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Gavzy
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Sangwon V
authors.initials: SV
authors.lastname: Kim
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Hall
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.|Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York 10003, USA.|Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, New York 10012, USA.|Simons Center for Data Analysis, Simons Foundation, New York, New York 10010, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Miraldi
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Ng
authors.affiliation: Isis Pharmaceuticals, Carlsbad, California 92010, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: Isis Pharmaceuticals, Carlsbad, California 92010, USA.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Rigo
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Meadows
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Nina R
authors.initials: NR
authors.lastname: Montoya
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Natalia G
authors.initials: NG
authors.lastname: Herrera
authors.affiliation: Instituto Gulbenkian de Ciencia, Oeiras 2780-156, Portugal.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Domingos
authors.affiliation: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, USA.
authors.forename: Fraydoon
authors.initials: F
authors.lastname: Rastinejad
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Frances V
authors.initials: FV
authors.lastname: Fuller-Pace
authors.affiliation: Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York 10003, USA.|Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, New York 10012, USA.|Simons Center for Data Analysis, Simons Foundation, New York, New York 10010, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bonneau
authors.affiliation: Center for Personal Dynamic Regulomes, Stanford University, Stanford, California 94305, USA.
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
authors.forename: Oreste
authors.initials: O
authors.lastname: Acuto
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.|Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006197:Hair / Q000002:abnormalities; D006627:Hirschsprung Disease / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D009928:Organ Specificity; D010009:Osteochondrodysplasias / Q000151:congenital / Q000235:genetics; D000081207:Primary Immunodeficiency Diseases; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D002843:Chromatin; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D062085:RNA, Long Noncoding; C506751:Ddx5 protein, mouse; D053487:DEAD-box RNA Helicases