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 (KLF4) represses HDC promoter activity in a gastric cell line through both an upstream Sp1 binding GC box and down stream 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 (DAPA) 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 HDC promoter. Interestingly, deletion analysis and cotransfection assays indicate that mutation of upstream GC box or truncation of downstream gastrin responsive elements in HDC promoter disrupted the inhibitory effect of YY1 and SREBP-1a in an identical fashion. Furthermore, quantitative RT-PCR analysis indicated that gastrin treatment downregulated SREBP-1a gene expression and reduced DNA binding activity of SREBP in electrophoretic mobility shift assays (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 down stream gastrin responsive elements, and gastrin-induced activation of HDC gene expression is mediated at least partly through down-regulation of transcriptional repressors like SREBPs.