The Hdc GC box is critical for Hdc gene transcription and histamine-mediated anaphylaxis

Abstract

Histamine is a critical mediator of anaphylaxis, a neurotransmitter, and a regulator of gastric acid secretion. Histidine decarboxylase is a rate-limiting enzyme for histamine synthesis. However, in vivo regulation of Hdc, the gene that encodes histidine decarboxylase is poorly understood. We identified potential enhancers in the Hdc gene using H3K27a histone modification and chromatin accessibility; we assessed the enhancer activity of the potential enhancers in a reporter gene assay; and we deleted noncoding sequences that possessed enhancer activity using CRISPR sgRNA guides. Deletion of the GC box reduced Hdc gene transcription and histamine synthesis in the CFTL-15 mouse mast cell line and the LAD2 human mast cell line. Mast cells, basophils, brain cells, and stomach cells from GC box-deficient mice transcribed the Hdc gene much less than similar cells from wild-type mice and Hdc GC box-deficient mice failed to develop anaphylaxis. Thus, a GC box within the proximal enhancer in the mouse Hdc gene is essential for Hdc gene transcription, histamine synthesis, and histamine-mediated anaphylaxis in vivo. Our study also reveals a critical role of the GC box in human HDC gene transcription and histamine synthesis.