Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes.
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.
Wang
Hongyan
H
State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University School of Life Science, Shanghai 200433, China.
Ogawa
Masaki
M
Wood
Jennifer R
JR
Bartolomei
Marisa S
MS
Sammel
Mary D
MD
Kusanovic
Juan Pedro
JP
Walsh
Scott W
SW
Romero
Roberto
R
Strauss
Jerome F
JF
D001741:Black or African American / Q000235:genetics; D000650:Amnion / Q000166:cytology / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011401:Promoter Regions, Genetic
C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1