Yin yang 1 (YY1) represseshistidine decarboxylasegene expression with SREBP-1a in part through an upstream Sp1 site

Abstract

Histidine decarboxylase (HDC) is the enzyme that converts histidine to histamine, a bioamine that plays an important role in many physiological aspects including allergic responses, inflammation, neurotransmission, and gastric acid secretion. In previous studies, we demonstrated that Kruppel-like factor 4 represses HDC promoter activity in a gastric cell line through both an upstream Sp1-binding GC box (GGGCGG sequence) and downstream gastrin-responsive elements. In the current study, Yin Yang 1 (YY1), a pleiotropic transcriptional factor, was also shown in cotransfection assays to repress HDC promoter activity through the upstream GC box. DNA affinity purification assay demonstrated that YY1 was pulled down specifically by the upstream GC box. In addition, sterol-responsive element-binding protein 1a (SREBP-1a), a transcriptional factor that binds YY1, represses the HDC promoter. Interestingly, deletion analysis and cotransfection assays indicated that mutation of the upstream GC box or truncation of downstream gastrin-responsive elements in the HDC promoter disrupted the inhibitory effect of YY1 and SREBP-1a in an identical fashion. Furthermore, quantitative real-time PCR analysis indicated that gastrin treatment downregulated SREBP-1a gene expression and reduced the DNA binding activity of SREBP in EMSAs. Taken together, these results suggest that YY1 and SREBP-1a form a complex to inhibit HDC gene expression through both the upstream GC box and downstream gastrin-responsive elements and gastrin-induced activation of HDC gene expression is mediated at least partly through downregulation of transcriptional repressors such as SREBPs.