DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions

Wendy Huang, Benjamin Thomas, Ryan A. Flynn, Samuel J. Gavzy, Lin Wu, Sangwon V. Kim, Jason A. Hall, Emily R. Miraldi, Charles P. Ng, Frank Rigo, Sarah Meadows, Nina R. Montoya, Natalia G. Herrera, Ana I. Domingos, Fraydoon Rastinejad, Richard M. Myers, Frances V. Fuller-Pace, Richard Bonneau, Howard Y. Chang, Oreste Acuto and Dan R. Littman ()
Additional contact information
Wendy Huang: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Benjamin Thomas: Sir William Dunn School of Pathology, University of Oxford
Ryan A. Flynn: Center for Personal Dynamic Regulomes, Stanford University
Samuel J. Gavzy: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Lin Wu: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Sangwon V. Kim: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Jason A. Hall: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Emily R. Miraldi: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Charles P. Ng: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Frank Rigo: Isis Pharmaceuticals
Sarah Meadows: HudsonAlpha Institute for Biotechnology
Nina R. Montoya: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Natalia G. Herrera: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Ana I. Domingos: Instituto Gulbenkian de Ciencia
Fraydoon Rastinejad: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute
Richard M. Myers: HudsonAlpha Institute for Biotechnology
Frances V. Fuller-Pace: University of Dundee
Richard Bonneau: Center for Genomics and Systems Biology, New York University
Howard Y. Chang: Center for Personal Dynamic Regulomes, Stanford University
Oreste Acuto: Sir William Dunn School of Pathology, University of Oxford
Dan R. Littman: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine

Nature, 2015, vol. 528, issue 7583, 517-522

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature16193

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