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 W. 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 & 1 others Dan R. Littman

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)517-522
Number of pages6
JournalNature
Volume528
Issue number7583
DOIs
StatePublished - Dec 24 2015

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Long Noncoding RNA
Th17 Cells
RNA Helicases
Genes
DEAD-box RNA Helicases
Mutation
Cytoplasmic and Nuclear Receptors
Helper-Inducer T-Lymphocytes
Chromatin
Pathology
Ligands
Infection
Proteins
Cartilage-hair hypoplasia

ASJC Scopus subject areas

  • General

Cite this

Huang, W., Thomas, B., Flynn, R. A., Gavzy, S. J., Wu, L., Kim, S. V., ... Littman, D. R. (2015). DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature, 528(7583), 517-522. https://doi.org/10.1038/nature16193

DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. / Huang, Wendy; Thomas, Benjamin; Flynn, Ryan A.; Gavzy, Samuel J.; Wu, Lin; Kim, Sangwon V.; Hall, Jason A.; Miraldi, Emily R.; Ng, Charles P.; Rigo, Frank W.; Meadows, Sarah; Montoya, Nina R.; Herrera, Natalia G.; Domingos, Ana I.; Rastinejad, Fraydoon; Myers, Richard M.; Fuller-Pace, Frances V.; Bonneau, Richard; Chang, Howard Y.; Acuto, Oreste; Littman, Dan R.

In: Nature, Vol. 528, No. 7583, 24.12.2015, p. 517-522.

Research output: Contribution to journalArticle

Huang, W, Thomas, B, Flynn, RA, Gavzy, SJ, Wu, L, Kim, SV, Hall, JA, Miraldi, ER, Ng, CP, Rigo, FW, Meadows, S, Montoya, NR, Herrera, NG, Domingos, AI, Rastinejad, F, Myers, RM, Fuller-Pace, FV, Bonneau, R, Chang, HY, Acuto, O & Littman, DR 2015, 'DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions', Nature, vol. 528, no. 7583, pp. 517-522. https://doi.org/10.1038/nature16193
Huang W, Thomas B, Flynn RA, Gavzy SJ, Wu L, Kim SV et al. DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature. 2015 Dec 24;528(7583):517-522. https://doi.org/10.1038/nature16193
Huang, Wendy ; Thomas, Benjamin ; Flynn, Ryan A. ; Gavzy, Samuel J. ; Wu, Lin ; Kim, Sangwon V. ; Hall, Jason A. ; Miraldi, Emily R. ; Ng, Charles P. ; Rigo, Frank W. ; Meadows, Sarah ; Montoya, Nina R. ; Herrera, Natalia G. ; Domingos, Ana I. ; Rastinejad, Fraydoon ; Myers, Richard M. ; Fuller-Pace, Frances V. ; Bonneau, Richard ; Chang, Howard Y. ; Acuto, Oreste ; Littman, Dan R. / DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. In: Nature. 2015 ; Vol. 528, No. 7583. pp. 517-522.
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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.",
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AU - Chang, Howard Y.

AU - Acuto, Oreste

AU - Littman, Dan R.

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