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Nature. 2015 Dec 24;528(7583):517-22. doi: 10.1038/nature16193. Epub 2015 Dec 16.

DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions.

Author information

1
The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
2
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
3
Center for Personal Dynamic Regulomes, Stanford University, Stanford, California 94305, USA.
4
Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York 10003, USA.
5
Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, New York 10012, USA.
6
Simons Center for Data Analysis, Simons Foundation, New York, New York 10010, USA.
7
Isis Pharmaceuticals, Carlsbad, California 92010, USA.
8
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.
9
Instituto Gulbenkian de Ciencia, Oeiras 2780-156, Portugal.
10
Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, USA.
11
Division of Cancer Research, University of Dundee, Dundee DD1 9SY, UK.
12
Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.

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.

PMID:
26675721
PMCID:
PMC4762670
DOI:
10.1038/nature16193
[Indexed for MEDLINE]
Free PMC Article

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