Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes.
Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes.
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DOI：
10.1093/hmg/ddm381
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发表时间：
2008-04
影响因子：
3.5
通讯作者：
Hongyan Wang;Masaki Ogawa;J. Wood;M. Bartolomei;M. Sammel;J. Kusanovic;S. Walsh;R. Romero;J. Strauss
中科院分区：
文献类型：
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作者：
Hongyan Wang;Masaki Ogawa;J. Wood;M. Bartolomei;M. Sammel;J. Kusanovic;S. Walsh;R. Romero;J. Strauss
纤维状胶原的降解被认为与正常分娩期间和胎膜过早破裂时的胎膜破裂有关。基质金属蛋白酶1（MMP 1）是参与细胞外基质周转的关键酶，MMP 1启动子的遗传变异与早产胎膜早破（PPROM）的风险相关。我们确定了表观遗传因素是否有助于控制MMP 1在人羊膜中的表达。在羊膜成纤维细胞中，用5-氮杂-2 '-脱氧胞苷抑制DNA甲基化导致MMP 1基因转录显著增加，并且MMP 1产生显著增加。这些效应与MMP 1启动子中特定位点（-1538）的DNA甲基化降低相关。在羊膜中该位点的DNA甲基化在胎膜过早破裂的较大百分比中降低。在MMP 1启动子区还发现了一个新的T > C单核苷酸多态性（SNP）[AF007878.1（MMP 1）：g.3447T>C]。次要C等位基因在体内总是甲基化的，并且当甲基化时，导致对羊膜成纤维细胞中的核蛋白的亲和力增加。通过质粒转染研究和染色质免疫沉淀试验，使用T > C SNP杂合的羊膜成纤维细胞，评估次要C等位基因的启动子活性降低。在一项病例对照研究中，发现次要C等位基因对PPROM具有保护作用，与其降低的启动子功能一致。我们的结论是，除了遗传变异，DNA甲基化在控制MMP 1的表达和不良产科结局的风险中发挥作用。
Degradation of fibrillar collagens is believed to be involved in the rupture of the fetal membranes during normal parturition and when the membranes rupture prematurely. Matrix metalloproteinase 1 (MMP1) is a key enzyme involved in extracellular matrix turnover, and genetic variation in the MMP1 promoter is associated with the risk of preterm premature rupture of membranes (PPROM). We determined whether epigenetic factors contribute to the control of MMP1 expression in the human amnion. Inhibition of DNA methylation with 5-aza-2'-deoxycytidine in amnion fibroblasts resulted in significantly increased MMP1 gene transcription, and an associated significant increase in MMP1 production. These effects were correlated with reduced DNA methylation at a particular site (-1538) in the MMP1 promoter. DNA methylation at this site in amnion was reduced in a larger percentage of fetal membranes that ruptured prematurely. A new T > C single nucleotide polymorphism (SNP) [AF007878.1 (MMP1):g.3447T>C] in the MMP1 promoter was also identified. The minor C allele was always methylated in vivo, and when methylated, resulted in increased affinity for a nuclear protein in amnion fibroblasts. The minor C allele had reduced promoter activity as assessed by plasmid transfection studies and chromatin immunoprecipitation assays using amnion fibroblasts heterozygous for the T > C SNP. In a case-control study, the minor C allele was found to be protective against PPROM, consistent with its reduced promoter function. We conclude that in addition to genetic variation, DNA methylation plays a role in controlling MMP1 expression and risk of an adverse obstetrical outcome.