Human Molecular Genetics Advance Access originally published online on January 4, 2008
Human Molecular Genetics 2008 17(8):1087-1096; doi:10.1093/hmg/ddm381
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Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes
1 State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University School of Life Science, Shanghai 200433, China 2 Center for Research on Reproduction and Women’s Health 3 Department of Cell and Developmental Biology 4 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA 19104, USA 5 Perinatology Research Branch, NICHD, Hutzel Hospital, Detroit, MI 48201, USA 6 Department of Obstetrics and Gynecology, Virginia Commonwealth University, MCV Campus, Sanger Hall, First Floor, Room 1-071, 1101 East Marshall Street, PO Box 980565, Richmond, VA 23298, USA
* To whom correspondence should be addressed. Tel: +1 8048289788; Fax: +1 8048287628; Email: jfstrauss{at}vcu.edu
Received November 26, 2007; Accepted December 20, 2007
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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