The transcription factors GATA2 and MITF regulate Hdc gene expression in mast cells and are required for IgE/mast cell-mediated anaphylaxis

Publication date: Available online 24 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Yapeng Li, Bing Liu, Laura Harmacek, Zijie Long, Jinyi Liang, Kara Lukin, Sonia M. Leach, Brian O'Connor, Anthony N. Gerber, James Hagman, Axel Roers, Fred D. Finkelman, Hua Huang
BackgroundHistamine 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.ObjectiveWe 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.Methodsmice 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.ResultsConnective 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.ConclusionThe transcription factors GATA2 and MITF regulate Hdc gene expression in mast cells and are required for IgE/mast cell-mediated anaphylaxis.

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