转录因子 GATA2 和小眼畸形相关转录因子调节肥大细胞中的 Hdc 基因表达，是 IgE/肥大细胞介导的过敏反应所必需的。
The transcription factors GATA2 and microphthalmia-associated transcription factor regulate Hdc gene expression in mast cells and are required for IgE/mast cell-mediated anaphylaxis.
机构信息
Department of Biomedical Research, National Jewish Health, Denver, Colo.
Department of Biomedical Research, National Jewish Health, Denver, Colo; Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
出版信息
J Allergy Clin Immunol. 2018 Oct;142(4):1173-1184. doi: 10.1016/j.jaci.2017.10.043. Epub 2017 Dec 24.
BACKGROUND
Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis. Histamine is synthesized by decarboxylating the amino acid histidine, a reaction catalyzed by the histidine decarboxylase (Hdc) gene-encoded enzyme HDC. However, regulation of the Hdc gene in mast cells is poorly understood.
OBJECTIVE
We sought to investigate the in vivo regulation of IgE/mast cell-mediated anaphylaxis by the transcription factors GATA2 and microphthalmia-associated transcription factor (MITF) and the mechanisms by which GATA2 and MITF regulate Hdc gene expression in mouse and human mast cells.
METHODS
Mice deficient in the transcription factors Gata2, aryl hydrocarbon receptor (Ahr), aryl hydrocarbon receptor repressor (Ahrr), or basic helix-loop-helix family member E40 (Bhlhe40) were assessed for anaphylactic reactions. Chromatin immunoprecipitation sequencing analysis identified putative Hdc enhancers. Luciferase reporter transcription assay confirmed enhancer activities of putative enhancers in the Hdc gene. The short hairpin RNA knockdown approach was used to determine the role of MITF in regulating mouse and human HDC gene expression.
RESULTS
Connective tissue mast cell-specific Gata2-deficient mice did not have IgE/mast cell-mediated anaphylaxis. GATA2 induced the expression of Mitf, Ahr, Ahrr, and Bhlhe40 in mast cells. MITF, but not AHR, AHRR, or BHLHE40, was required for anaphylaxis. MITF bound to an enhancer located 8.8 kb upstream of the transcription start site of the Hdc gene and directed enhancer activity. MITF overexpression largely restored Hdc gene expression in the Gata2-deficient mast cells. In the human mast cell line LAD2, MITF was required for the HDC gene expression and histamine synthesis.
CONCLUSION
The transcription factors GATA2 and MITF regulate Hdc gene expression in mast cells and are required for IgE/mast cell-mediated anaphylaxis.
背景
组织胺是 IgE/肥大细胞介导的过敏反应的关键介质。组织胺是由氨基酸组氨酸脱羧生成的，这一反应由组氨酸脱羧酶（Hdc）基因编码的酶 HDC 催化。然而，肥大细胞中 Hdc 基因的调控机制尚不清楚。
目的
我们试图研究转录因子 GATA2 和小眼畸形相关转录因子（MITF）对 IgE/肥大细胞介导的过敏反应的体内调节作用，以及 GATA2 和 MITF 调节小鼠和人肥大细胞中 Hdc 基因表达的机制。
方法
评估了转录因子 Gata2、芳烃受体（Ahr）、芳烃受体阻遏物（Ahrr）或基本螺旋-环-螺旋家族成员 E40（Bhlhe40）缺失的小鼠的过敏反应。染色质免疫沉淀测序分析鉴定了 Hdc 增强子的假定位置。荧光素酶报告基因转录测定证实了 Hdc 基因中假定增强子的活性。采用短发夹 RNA 敲低方法确定了 MITF 在调节小鼠和人 HDC 基因表达中的作用。
结果
结缔组织肥大细胞特异性 Gata2 缺失的小鼠没有 IgE/肥大细胞介导的过敏反应。GATA2 在肥大细胞中诱导 Mitf、Ahr、Ahrr 和 Bhlhe40 的表达。MITF，但不是 AHR、AHRR 或 BHLHE40，是过敏反应所必需的。MITF 结合到 Hdc 基因转录起始位点上游 8.8 kb 的增强子上，并指导增强子活性。MITF 过表达在很大程度上恢复了 Gata2 缺失的肥大细胞中 Hdc 基因的表达。在人肥大细胞系 LAD2 中，MITF 是 HDC 基因表达和组氨酸合成所必需的。
结论
转录因子 GATA2 和 MITF 调节肥大细胞中 Hdc 基因的表达，是 IgE/肥大细胞介导的过敏反应所必需的。
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