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J Allergy Clin Immunol. 2018 Oct;142(4):1173-1184. doi: 10.1016/j.jaci.2017.10.043. Epub 2017 Dec 24.

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.

Author information

1
Department of Biomedical Research, National Jewish Health, Denver, Colo.
2
Department of Biomedical Research, National Jewish Health, Denver, Colo; Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
3
Center for Genes, Environment and Health, National Jewish Health, Denver, Colo.
4
Department of Biomedical Research, National Jewish Health, Denver, Colo; Department of Hematology, The Third Affiliated Hospital, Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
5
Department of Biomedical Research, National Jewish Health, Denver, Colo; Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
6
Department of Biomedical Research, National Jewish Health, Denver, Colo; Center for Genes, Environment and Health, National Jewish Health, Denver, Colo.
7
Department of Biomedical Research, National Jewish Health, Denver, Colo; Department of Medicine, National Jewish Health, Denver, Colo.
8
Department of Biomedical Research, National Jewish Health, Denver, Colo; Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Colo.
9
Institute for Immunology, Technische Universit ät Dresden, Dresden, Germany.
10
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Immunology, Allergy and Rheumatology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
11
Department of Biomedical Research, National Jewish Health, Denver, Colo; Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Colo. Electronic address: huangh@njhealth.org.

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.

KEYWORDS:

GATA2; Mast cell; anaphylaxis; connective tissue mast cell; enhancer; histamine synthesis; histidine decarboxylase; microphthalmia-associated transcription factor

PMID:
29277702
PMCID:
PMC6291018
[Available on 2019-10-01]
DOI:
10.1016/j.jaci.2017.10.043

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