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 - 05/10/18
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Mast cell, connective tissue mast cell, GATA2, microphthalmia-associated transcription factor, histidine decarboxylase, enhancer, anaphylaxis, histamine synthesis
Abbreviations used : AHR, AHRR, BHLHE40, BMMC, ChIP-seq, CTMC, HDC, H3K27Ac, H3K4me1, MITF, MMCP-1, PCA, PCMC, pre-BMP, PSA, qPCR, shRNA, TNP, YFP
Plan
| Supported by grants from the National Institutes of Health (R01AI107022 and RO1AI083986 to H.H., R01 AI098417 to J.H., and R01AI113162 to F.D.F.), funds provided by the China Scholarship Council (201606385033 to Z.L. and 201406270087 to B.L.), and funds provided by Sun Yet-Sen University (to J.L.). |
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| Disclosure of potential conflict of interest: Y. Li and H. Huang have received grants from the National Institutes of Health (NIH; R01AI107022 and RO1AI083986). B. Liu has received grants from the NIH (R01AI107022 and RO1AI083986) and the China Scholarship Council (201406270087). Z. Long has received grants from the NIH (R01AI107022 and RO1AI083986) and the China Scholarship Council (201606385033). J. Liang has received grants from the NIH (R01AI107022 and RO1AI083986) and Sun Yat-Sen University. F. D. Finkelman has consultant arrangements with Vedanta Bioscience; is employed by the University of Cincinnati; has received grants from the National Institutes of Health and Food Allergy Research & Education; and has 3 patents from the University of Cincinnati and the Cincinnati Children's Hospital Medical Center. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 4
P. 1173-1184 - octobre 2018 Retour au numéro
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