• A Corrigendum to this article was published on 20 January 2016
  • This article was retracted on 04 July 2018

This article has been updated

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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Change history

  • 04 July 2018

    This Article has been retracted; see accompanying Retraction. Corrected online 20 January 2016. In this Article, author Frank Rigo was incorrectly listed with a middle initial; this has been corrected in the online versions of the paper.

Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

RNA-seq, TRAP-seq, RIP-seq, and ChIRP-seq data have been deposited in the Gene Expression Omnibus under accession number GSE70110.

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Acknowledgements

We thank M. V. Pokrovskii for unpublished ATAC-seq data and L. X. Garmire for suggestions on our manuscript. This work was supported by a Cancer Research Institute Irvington Postdoctoral Fellowship (W.H.), Institutional NRSA T32 CA009161_Levy (W.H.), National Multiple Sclerosis Society postdoctoral fellowship FG 2089-A-1 (L.W.), Career Development Award (329388) from the Crohn’s and Colitis Foundation of America (S.V.K.), Dale and Betty Frey Fellowship of the Damon Runyon Cancer Research Foundation 2105-12 (J.A.H.), HHMI Exceptional Research Opportunities Program (N.R.M. and N.H.), NIH F30 1F30CA189514-01 (R.A.F.), NIH P50-HG007735 and R01HG004361 (H.Y.C.), NIH R01AI080885 (D.R.L.), NIH R01DK103358 (R.B. and D.R.L.), and the Howard Hughes Medical Institute (H.Y.C. and D.R.L.).

Author information

Affiliations

  1. The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA

    • Wendy Huang
    • , Samuel J. Gavzy
    • , Lin Wu
    • , Sangwon V. Kim
    • , Jason A. Hall
    • , Emily R. Miraldi
    • , Charles P. Ng
    • , Nina R. Montoya
    • , Natalia G. Herrera
    •  & Dan R. Littman
  2. Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK

    • Benjamin Thomas
    •  & Oreste Acuto
  3. Center for Personal Dynamic Regulomes, Stanford University, Stanford, California 94305, USA

    • Ryan A. Flynn
    •  & Howard Y. Chang
  4. Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York 10003, USA

    • Emily R. Miraldi
    •  & Richard Bonneau
  5. Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, New York 10012, USA

    • Emily R. Miraldi
    •  & Richard Bonneau
  6. Simons Center for Data Analysis, Simons Foundation, New York, New York 10010, USA

    • Emily R. Miraldi
    •  & Richard Bonneau
  7. Isis Pharmaceuticals, Carlsbad, California 92010, USA

    • Frank Rigo
  8. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA

    • Sarah Meadows
    •  & Richard M. Myers
  9. Instituto Gulbenkian de Ciencia, Oeiras 2780-156, Portugal

    • Ana I. Domingos
  10. Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, USA

    • Fraydoon Rastinejad
  11. Division of Cancer Research, University of Dundee, Dundee DD1 9SY, UK

    • Frances V. Fuller-Pace
  12. Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA

    • Dan R. Littman

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Contributions

W.H. and D.R.L. designed experiments, analysed data and wrote the manuscript with input from the co-authors; B.T. and O.A. performed mass spectrometry studies; F.Ri. designed and synthesized control and Rmrp ASOs; S.J.G. and L.W. performed MOG-EAE immunization and blinded scoring; S.V.K. performed blinded histology scoring on colitis sections; W.H. and A.I.D. designed and performed ribosome TRAP-seq studies. S.M. and R.M.M. performed library preparation for RNA sequencing studies; N.R.M. and N.G.H. performed microscopy studies; F.Ra. provided recombinant full length His-tagged hRORγt, and F.V.F.-P. generated DDX5 conditional mutant animals. J.A.H. performed RORγt ChIP studies. C.P.N performed DDX5 studies in the thymus. R.A.F., W.H. and H.Y.C. performed ChIRP-seq experiments. E.R.M and R.B. performed statistical analyses on ChIRP-seq experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dan R. Littman.

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https://doi.org/10.1038/nature16193

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