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MGP gene mutations cause Keutel syndrome with abnormal calcifications across cartilage, lungs, brain, and vasculature. MGP is also dysregulated in multiple cancers. Bioinformatic analysis identified CpG-overlapping transcription factor binding sites in the MGP promoter, including YY1, GATA1, and C/EBPα. Functional luciferase reporter assays showed that YY1, GATA1, and C/EBPα repress MGP promoter activity, while RUNX2 activates it.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/transcriptional-regulation-of-the-human-mgp-promoter-identification-of-downstream-repressors/331632/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/transcriptional-regulation-of-the-human-mgp-promoter-identification-of-downstream-repressors/331632.png","ImageObject",300,407,{"name":92,"@type":93},"Genevieve","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What biological role does MGP play and why is it important?","Question",{"text":112,"@type":113},"MGP functions as a vitamin K-dependent inhibitor of ectopic calcification, primarily impacting cartilage and the vascular system. Its dysregulation contributes to multiple cancers and is linked to Keutel syndrome when the MGP gene is mutated.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which transcription factors were identified as interacting with the MGP promoter?",{"text":117,"@type":113},"Bioinformatic approaches identified CpG dinucleotide-containing TF binding sites for YY1, GATA1, and C/EBPα. Functional tests also examined RUNX2 as an activating factor.",{"name":119,"@type":110,"acceptedAnswer":120},"How do YY1, GATA1, and C/EBPα affect MGP promoter activity?",{"text":121,"@type":113},"Transient transfection luciferase assays showed that co-transfection with YY1, GATA1, and C/EBPα represses the MGP promoter. 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Leonor Cancela 1,2,3 and Natércia Conceição 1,2,3, *  \nCitation: Caiado, H.; Cancela, M.L.; Conceição, N. Transcriptional Regulation of the Human MGP Promoter: Identification of Downstream Repressors. Int. J. Mol. Sci. 2024, 25, 12597. [https://](https://)[ ](https://)[doi.org/10.3390/ijms252312597](doi.org/10.3390/ijms252312597)  \nAcademic Editor: Mikhail  \nI. Churnosov  \nReceived: 27 September 2024  \nRevised: 18 November 2024  \nAccepted: 20 November 2024  \nPublished: 23 November 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Center of Marine Sciences (CCMAR), University of Algarve, 8005-139 Faro, Portugal; [helena.isabel.caiado@gmail.com](helena.isabel.caiado@gmail.com) (H.C.); [lcancela@ualg.pt](lcancela@ualg.pt) (M.L.C.)  \n2 Faculty of Medicine and Biomedical Sciences, University of Algarve, 8005-139 Faro, Portugal  \n3 Algarve Biomedical Center, University of Algarve, 8005-139 Faro, Portugal  \n* [Correspondence: nconcei@ualg.pt](Correspondence: nconcei@ualg.pt)  \nAbstract: 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.  \nKeywords: MGP; transcriptional regulation; methylation; YY1; GATA1; C/EBPα  \n1. Introduction  \nMatrix Gla protein (MGP) is a member of the family of vitamin K-dependent Gla proteins mainly associated with the extracellular matrix. The MGP gene located on chromosome 12p12.3 [1] is highly expressed by vascular smooth muscle cells (VSMCs) [2] and chondrocytes [3] . The MGP function was clarified through the identification of mutations in MGP that lead to the Keutel syndrome [4] . Recently, two new heterozygous variants were identified in the MGP gene altering the Cys19 residue in the translated protein responsible for autosomal dominant spondyloepiphyseal dysplasia [5] . Consistent with the functional importance of MGP in physiology, deregulated expression of MGP has been reported to correlate with the development of various other pathologies including colorectal, ovarian, lung, and breast cancers [6] .  \nDespite the knowledge of the involvement of MGP in diverse cellular events, the mechanisms regulating the expression of the MGP gene remain largely unknown. The regulation of the MGP promoter has bee","cbCaibzlfjZgJGN2","https://ap.wps.com/l/cbCaibzlfjZgJGN2","pdf",3204096,"English","# Abstract\n# Keywords\n# Introduction\n## Background on MGP and Keutel syndrome\n## Knowledge gaps in MGP promoter regulation\n## Objective and experimental strategy","[{\"question\":\"What biological role does MGP play and why is it important?\",\"answer\":\"MGP functions as a vitamin K-dependent inhibitor of ectopic calcification, primarily impacting cartilage and the vascular system. Its dysregulation contributes to multiple cancers and is linked to Keutel syndrome when the MGP gene is mutated.\"},{\"question\":\"Which transcription factors were identified as interacting with the MGP promoter?\",\"answer\":\"Bioinformatic approaches identified CpG dinucleotide-containing TF binding sites for YY1, GATA1, and C/EBPα. Functional tests also examined RUNX2 as an activating factor.\"},{\"question\":\"How do YY1, GATA1, and C/EBPα affect MGP promoter activity?\",\"answer\":\"Transient transfection luciferase assays showed that co-transfection with YY1, GATA1, and C/EBPα represses the MGP promoter. In contrast, co-transfection with RUNX2 activates it.\"}]","Transcriptional Regulation of the Human MGP Promoter - Identification of Downstream Repressors | PDF",1789994377,48]