title: Allelic variation of the MMP3 promoter affects transcription activity through the transcription factor C-MYB in human brain arteriovenous malformations.
abstract: MMPs comprise a family of proteolytic enzymes that degrade pericellular substances, which may result in the destabilization of vessels and related to the development of brain arteriovenous malformations (BAVM). MMP3 is a key member of this family, overexpressed in BAVM tissues, and a single nucleotide polymorphism within MMP3, -709A>G (rs522616), is significantly associated with the risk of BAVM. In this study, we aimed to investigate the mechanism through which the polymorphism rs522616 regulates the expression of MMP3. Our results showed that -709A led to a over 2-fold higher transcriptional activity compared with the G allele (P<0.05) and this transcriptional activity can be depressed by co-transfecting cells with competitive DNA fragments containing -709A but not -709G. Bioinformatics analyses suggested that the transcription factor C-MYB might bind to the area around rs522616. Overexpressed C-MYB significantly increased the transcriptional activity of -709A compared with -709G or controls that did not overexpress c-myb (P<0.01) in HEK293 and HUVEC cells. ChIP assays indicated that C-MYB bound to the SNP region in the two cell lines and three BAVM tissue samples. Together, these data indicated that C-MYB can bind to the -709A allele of the MMP3 promoter, activate its transcription and lead to a higher expression of this gene. This novel hypothesis, supported by molecular evidence, explains how this SNP affects MMP3 promoter function and results in a risk of BAVM development.
authors.affiliation: State Key Laboratory of Genetic Engineering, Fudan-VARI Genetic Epidemiology Center and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes for Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Huai
authors.forename: Jianping
authors.initials: J
authors.lastname: Song
authors.forename: Zengyi
authors.initials: Z
authors.lastname: Ma
authors.forename: Xuanfeng
authors.initials: X
authors.lastname: Qin
authors.forename: Peiliang
authors.initials: P
authors.lastname: Li
authors.forename: Hongyan
authors.initials: H
authors.lastname: Chen
authors.forename: Fan
authors.initials: F
authors.lastname: Zhao
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
authors.forename: Donglei
authors.initials: D
authors.lastname: Song
authors.forename: Ying
authors.initials: Y
authors.lastname: Mao
authors.forename: Xiao
authors.initials: X
authors.lastname: Song
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities / Q000201:enzymology / Q000473:pathology; D004247:DNA / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D002538:Intracranial Arteriovenous Malformations / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D020598:Proto-Oncogene Proteins c-myb; D004247:DNA; D008156:Luciferases; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3