Transcriptional Regulation of the Human MGP Promoter: Identification of Downstream Repressors

Matrix Gla protein (MGP) is a vitamin K-dependent γ-carboxylated protein that was initially identified as a physiological inhibitor of ectopic calcification, primarily affecting cartilage and the vascular system. Mutations in the MGP gene were found to be responsible for the Keutel syndrome, a condition characterized by abnormal calcifications in the cartilage, lungs, brain, and vascular system. MGP has been shown to be dysregulated in several tumors, including cervical, ovarian, urogenital, and breast cancers. Using bioinformatic approaches, transcription factor binding sites (TFBSs) containing CpG dinucleotides were identified in the MGP promoter, including those for YY1, GATA1, and C/EBPα. We carried out functional tests using transient transfections with a luciferase reporter assay, primarily for the transcription factors YY1, GATA1, C/EBPα, and RUNX2. By co-transfection analysis, we found that YY1, GATA1, and C/EBPα repressed the MGP promoter. Furthermore, the co-transfection with RUNX2 activated the MGP promoter. In addition, MGP expression is negatively or positively correlated with the studied TFs' expression levels in several cancer types. This study provides novel insights into MGP regulation by demonstrating that YY1, GATA1, and C/EBPα are negative regulators of the MGP promoter, and DNA methylation may influence their activity. The dysregulation of these mechanisms in cancer should be further elucidated.