Journal Article

DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions

Thomas, Benjamin, Huang, Wendy, Kim, Sangwon V., Bonneau, Richard, Meadows, Sarah, Fuller-Pace, Frances V., Gavzy, Samuel J., Ng, Charles P., Herrera, Natalia G., Rastinejad, Fraydoon, Flynn, Ryan A., Acuto, Oreste, Miraldi, Emily R., Rigo, Frank, Domingos, Ana I., Chang, Howard Y., Montoya, Nina R., Littman, Dan R., Wu, Lin, Hall, Jason A., Myers, Richard M.

2015

Overview

T helper 17 (T H 17) 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 T H 17 genes, and is required for T H 17-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 T H 17-dependent diseases. The ability of the DEAD-box RNA helicase DDX5 to interact with master transcription factor RORγt is dependent on binding of the long noncoding RNA Rmrp ; the DDX5–RORγt complex coordinates transcription of selective T H 17 genes and is required for the pathogenicity of T H 17 cells. Modifiers of T H 17 cell pathogenicity The ability of the DEAD-box RNA helicase DDX5 to interact with master transcription factor RORγt is shown to be dependent on binding of the long noncoding RNA Rmrp . The DDX5–RORγt complex coordinates transcription of selective T-helper 17 (T H 17) genes, and is required for the pathogenicity of T H 17 lymphocytes. The discovery of this relationship between an RNA helicase and a long noncoding RNA in complex provide new insight into the role of transcriptional regulation and suggests new avenues for research into T H 17-dependent diseases.

• Publisher: Nature Publishing Group UK
• Subject: 631/250/2502 / 631/337/384 / Animals / Chromatin - genetics / Chromatin - metabolism / DEAD-box RNA Helicases - genetics / DEAD-box RNA Helicases - metabolism / Female / Gene Expression Regulation - genetics / Hair - abnormalities / Hirschsprung Disease - genetics / Humanities and Social Sciences / Humans / Immunologic Deficiency Syndromes - genetics / Inflammation - immunology / Inflammation - pathology / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Mutation - genetics / Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism / Organ Specificity / Osteochondrodysplasias - congenital / Osteochondrodysplasias - genetics / Primary Immunodeficiency Diseases / Protein Binding / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / Science / Th17 Cells - immunology / Th17 Cells - metabolism / Transcription, Genetic - genetics