Retinoic Acid Receptor Alpha Represses a Th9 Transcriptional and Epigenomic Program to Reduce Allergic Pathology

Daniella M. Schwartz, Taylor K. Farley, Nathan Richoz, Chen Yao, Han Yu Shih, Franziska Petermann, Yuan Zhang, Hong Wei Sun, Erika Hayes, Yohei Mikami, Kan Jiang, Fred P. Davis, Yuka Kanno, Joshua D. Milner, Richard Siegel, Arian Laurence, Françoise Meylan, John J. O'Shea

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10 Citations (Scopus)

Abstract

CD4+ T helper (Th) differentiation is regulated by diverse inputs, including the vitamin A metabolite retinoic acid (RA). RA acts through its receptor RARα to repress transcription of inflammatory cytokines, but is also essential for Th-mediated immunity, indicating complex effects of RA on Th specification and the outcome of the immune response. We examined the impact of RA on the genome-wide transcriptional response during Th differentiation to multiple subsets. RA effects were subset-selective and were most significant in Th9 cells. RA globally antagonized Th9-promoting transcription factors and inhibited Th9 differentiation. RA directly targeted the extended Il9 locus and broadly modified the Th9 epigenome through RARα. RA-RARα activity limited murine Th9-associated pulmonary inflammation, and human allergic inflammation was associated with reduced expression of RA target genes. Thus, repression of the Th9 program is a major function of RA-RARα signaling in Th differentiation, arguing for a role for RA in interleukin 9 (IL-9) related diseases.

Original languageEnglish
Pages (from-to)106-120.e10
JournalImmunity
Volume50
Issue number1
DOIs
Publication statusPublished - 2019 Jan 15

Keywords

  • ATAC-seq
  • ChIP-seq
  • Enhancers
  • Interleukin 9
  • Interleukins
  • RNA sequencing
  • Retinoic acid
  • T helper cells
  • Th9 cells
  • vitamin A

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Schwartz, D. M., Farley, T. K., Richoz, N., Yao, C., Shih, H. Y., Petermann, F., Zhang, Y., Sun, H. W., Hayes, E., Mikami, Y., Jiang, K., Davis, F. P., Kanno, Y., Milner, J. D., Siegel, R., Laurence, A., Meylan, F., & O'Shea, J. J. (2019). Retinoic Acid Receptor Alpha Represses a Th9 Transcriptional and Epigenomic Program to Reduce Allergic Pathology. Immunity, 50(1), 106-120.e10. https://doi.org/10.1016/j.immuni.2018.12.014