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.
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.
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DOI：
10.1016/j.jaci.2017.10.043
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Li Y;Liu B;Harmacek L;Long Z;Liang J;Lukin K;Leach SM;O'Connor B;Gerber AN;Hagman J;Roers A;Finkelman FD;Huang H
组胺是IgE/肥大细胞介导的过敏反应的关键介质。组胺是通过组氨酸脱羧合成的，这是一个由Hdc基因编码的组氨酸脱羧酶催化的反应。然而，肥大细胞中Hdc基因的调控知之甚少。我们试图研究转录因子GATA 2和MITF对IgE/肥大细胞介导的过敏反应的体内调节，以及GATA 2和MITF调节小鼠和人肥大细胞中Hdc基因表达的机制。评估转录因子Gata 2、Ahr、Ahrr或Bhlhe 40缺陷的小鼠的过敏反应。染色质免疫沉淀测序分析确定了推定的Hdc增强子。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增强子活性。使用shRNA敲低方法来确定MITF在调节小鼠和人HDC基因表达中的作用。结缔组织肥大细胞（CTMC）特异性Gata 2缺陷小鼠未能发展IgE/肥大细胞介导的过敏反应。GATA 2诱导肥大细胞表达Mitf、Ahr、Ahrr和Bhlhe 40。过敏反应需要MITF，而不是AHR、AHRR或BHLHE 40。MITF与位于Hdc基因转录起始位点上游8.8 kb的增强子结合，并指导增强子活性。MITF过表达在很大程度上恢复了Gata 2缺陷肥大细胞中Hdc基因的表达。在人肥大细胞系LAD 2中，MITF是HDC基因表达和组胺合成所必需的。转录因子GATA 2和MITF调节肥大细胞中的Hdc基因表达，并且是IgE/肥大细胞介导的过敏反应所需的。我们的研究表明，转录因子GATA 2和MITF主要通过调节肥大细胞中的Hdc基因在IgE/肥大细胞介导的过敏反应中发挥重要作用。
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 Hdc-gene encoded enzyme histidine decarboxylase. However, regulation of the Hdc gene in mast cells is poorly understood. We sought to investigate the in vivo regulation of IgE/mast cell mediated anaphylaxis by transcription factors GATA2 and MITF and the mechanisms by which GATA2 and MITF regulate Hdc gene expression in mouse and human mast cells. mice deficient in the transcription factors Gata2, Ahr, Ahrr, or 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 shRNA knock down approach was used to determine the role of MITF in regulating mouse and human HDC gene expression. Connective tissue mast cell (CTMC)-specific Gata2 deficient mice failed to develop 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 human mast cell line LAD2, MITF was required for the HDC gene expression and histamine synthesis. The transcription factors GATA2 and MITF regulate Hdc gene expression in mast cells and are required for IgE/mast cell-mediated anaphylaxis. Our study demonstrates that the transcription factors GATA2 and MITF play an essential role in IgE/mast cell-mediated anaphylaxis mainly by regulating Hdc gene in mast cells.
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