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The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in TH2 cells

Nature Immunology volume 12, pages 77–85 (2011)Cite this article

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Abstract

GATA-3 is a master regulator of T helper type 2 (TH2) differentiation. However, the molecular basis of GATA-3-mediated TH2 lineage commitment is poorly understood. Here we identify the DNase I–hypersensitive site 2 (HS2) element located in the second intron of the interleukin 4 locus (Il4) as a critical enhancer strictly controlled by GATA-3 binding. Mice lacking HS2 showed substantial impairment in their asthmatic responses and their production of IL-4 but not of other TH2 cytokines. Overexpression of Gata3 in HS2-deficient T cells failed to restore Il4 expression. HS2 deletion impaired the trimethylation of histone H3 at Lys4 and acetylation of histone H3 at Lys9 and Lys14 in the Il4 locus. Our results indicate that HS2 is the target of GATA-3 in regulating chromosomal modification of the Il4 locus and is independent of the Il5 and Il13 loci.

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Figure 1: Histone modification of the Il13 and Il4 loci and regulation of IL-4 by HS sites.
Figure 2: Antibody and asthmatic airway responses in HS2-deficient mice.
Figure 3: HS2 is critical for the primary production of IL-4 by MP T cells and NKT cells.
Figure 4: The HS2 enhancer regulates IL-4 production in TH2 cells.
Figure 5: The HS2 enhancer is required for GATA-3-mediated production of IL-4.
Figure 6: Histone H3 modification and binding of GATA-3 to the Il13 and Il4 loci.
Figure 7: HS2-deficient T cells have a defect in histone acetylation and methylation.

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Acknowledgements

We thank R. Locksley (University of California, San Francisco) for CNS-1-deficient mice on the BALB/c background; R. Abe (Tokyo University of Science) for the PV-1 mAb to CD28; T. Kitamura (Tokyo University) for Platinum-E packaging cells; and H. Fujimoto, Y. Hachiman, E. Hayashi and K. Ikari for technical assistance. Supported by a Grant-in-Aid-of-Scientific Research in Priority Areas of the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation; and RIKEN (Y.M.).

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  1. Shinya Tanaka and Yasutaka Motomura: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan

    Shinya Tanaka, Yasutaka Motomura, Yoshie Suzuki, Ryoji Yagi & Masato Kubo

  2. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Hiromasa Inoue

  3. Cytokine Project, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Shoichiro Miyatake

  4. Research Institute for Biological Sciences, Tokyo University of Science, Chiba, Japan

    Masato Kubo

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Contributions

S.T. built the initial constructs, generated mouse lines and confirmed mouse lines in vivo; Y.M. did ChIP analysis; Y.S. screened mouse lines; R.Y. built the initial constructs; H.I. did airway hyper-responsiveness experiments; S.M. distributed materials; and M.K. designed experiments, supervised the project and wrote the paper.

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Correspondence to Masato Kubo.

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Tanaka, S., Motomura, Y., Suzuki, Y. et al. The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in TH2 cells. Nat Immunol 12, 77–85 (2011). https://doi.org/10.1038/ni.1966

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