A distal enhancer of GATA3 regulates Th2 differentiation and allergic inflammation

• 成果类型: Article
• 署名作者: Kumagai, Takashi; Iwata, Arifumi; Furuya, Hiroki; Kato, Kodai; Okabe, Atsushi; Toda, Yosuke; Kanai, Mizuki; Fujimura, Lisa; Sakamoto, Akemi; Kageyama, Takahiro; Tanaka, Shigeru; Suto, Akira; Hatano, Masahiko; Kaneda, Atsushi; Nakajima, Hiroshi
• 署名单位: Chiba University; Chiba University; Chiba University; Chiba University; Chiba University; Chiba University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12097
• DOI: 10.1073/pnas.2320727121
• 发表日期: 2024-07-02
• 关键词: t-cells reveals; asthma; innate

摘要

Asthma is a widespread airway disorder where GATA3- dependent Type- 2 helper T (Th2) cells and group 2 innate lymphoid cells (ILC2s) play vital roles. Asthma- associated single nucleotide polymorphisms (SNPs) are enriched in a region located 926- 970 kb downstream from GATA3 in the 10p14 (hG900). However, it is unknown how hG900 affects the pathogenesis of allergic airway inflammation. To investigate the roles of the asthma- associated GATA3 enhancer region in experimental allergic airway inflammation, we first examined the correlation between GATA3 expression and the activation of the hG900 region was analyzed by flow cytometry and ChIP- qPCR. We found that The activation of enhancers in the hG900 region was strongly correlated to the levels of GATA3 in human peripheral generated by the CRISPR- Cas9 system, and the development and function of helper T cells and ILCs in mG900KO mice were analyzed in steady- state conditions and allergic airway inflammation induced by papain or house dust mite (HDM). The deletion of the mG900 did not affect the development of lymphocytes in steady- state conditions or allergic airway inflammation induced by papain. However, mG900KO mice exhibited reduced allergic inflammation and Th2 differentiation in the HDM- induced allergic airway inflammation. The analysis of the chromatin conformation around Gata3 by circular chromosome conformation capture coupled to high- throughput sequencing (4C- seq) revealed that the mG900 region interacted with the transcription start site of Gata3 with an influencing chromatin conformation in Th2 cells. These findings indicate that the mG900 region plays a pivotal role in Th2 differentiation and thus enhances allergic airway inflammation.