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

doi:10.1016/j.immuni.2018.12.014

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

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

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 language	English (US)
Pages (from-to)	106-120.e10
Journal	Immunity
Volume	50
Issue number	1
DOIs	https://doi.org/10.1016/j.immuni.2018.12.014
State	Published - Jan 15 2019
Externally published	Yes

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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10.1016/j.immuni.2018.12.014

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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

Schwartz, DM, Farley, TK, Richoz, N, Yao, C, Shih, HY, Petermann, F, Zhang, Y, Sun, HW, Hayes, E, Mikami, Y, Jiang, K, Davis, FP, Kanno, Y, Milner, JD, Siegel, R, Laurence, A, Meylan, F & O'Shea, JJ 2019, 'Retinoic Acid Receptor Alpha Represses a Th9 Transcriptional and Epigenomic Program to Reduce Allergic Pathology', Immunity, vol. 50, no. 1, pp. 106-120.e10. https://doi.org/10.1016/j.immuni.2018.12.014

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title = "Retinoic Acid Receptor Alpha Represses a Th9 Transcriptional and Epigenomic Program to Reduce Allergic Pathology",

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.",

keywords = "ATAC-seq, ChIP-seq, Enhancers, Interleukin 9, Interleukins, RNA sequencing, Retinoic acid, T helper cells, Th9 cells, vitamin A",

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

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month = jan,

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doi = "10.1016/j.immuni.2018.12.014",

language = "English (US)",

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T1 - Retinoic Acid Receptor Alpha Represses a Th9 Transcriptional and Epigenomic Program to Reduce Allergic Pathology

AU - Schwartz, Daniella M.

AU - Farley, Taylor K.

AU - Richoz, Nathan

AU - Yao, Chen

AU - Shih, Han Yu

AU - Petermann, Franziska

AU - Zhang, Yuan

AU - Sun, Hong Wei

AU - Hayes, Erika

AU - Mikami, Yohei

AU - Jiang, Kan

AU - Davis, Fred P.

AU - Kanno, Yuka

AU - Milner, Joshua D.

AU - Siegel, Richard

AU - Laurence, Arian

AU - Meylan, Françoise

AU - O'Shea, John J.

PY - 2019/1/15

Y1 - 2019/1/15

N2 - 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.

AB - 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.

KW - ATAC-seq

KW - ChIP-seq

KW - Enhancers

KW - Interleukin 9

KW - Interleukins

KW - RNA sequencing

KW - Retinoic acid

KW - T helper cells

KW - Th9 cells

KW - vitamin A

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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