Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes

State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University School of Life Science, Shanghai 200433, China.
Human Molecular Genetics (Impact Factor: 6.39). 04/2008; 17(8):1087-96. DOI: 10.1093/hmg/ddm381
Source: PubMed


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.

Download full-text


Available from: Jennifer R Wood,

Click to see the full-text of:

Article: Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes

436.55 KB

See full-text
  • Source
    • "Considering that the amniotic �uid is in a constantly changing state, it may be critical that the amnion properly responds to environmental cues from the amniotic �uid to accommodate the dynamic needs of the fetus, which could be mediated through epigenetic processes. A previous study by Wang et al. [15] has shown that matrix metalloproteinase 1 (MMP1), whose genetic variation is associated with susceptibility to PPROM [16], is regulated at the epigenetic level, "
    [Show abstract] [Hide abstract]
    ABSTRACT: The amnion is a specialized tissue in contact with the amniotic fluid, which is in a constantly changing state. To investigate the importance of epigenetic events in this tissue in the physiology and pathophysiology of pregnancy, we performed genome-wide DNA methylation profiling of human amnion from term (with and without labor) and preterm deliveries. Using the Illumina Infinium HumanMethylation27 BeadChip, we identified genes exhibiting differential methylation associated with normal labor and preterm birth. Functional analysis of the differentially methylated genes revealed biologically relevant enriched gene sets. Bisulfite sequencing analysis of the promoter region of the oxytocin receptor (OXTR) gene detected two CpG dinucleotides showing significant methylation differences among the three groups of samples. Hypermethylation of the CpG island of the solute carrier family 30 member 3 (SLC30A3) gene in preterm amnion was confirmed by methylation-specific PCR. This work provides preliminary evidence that DNA methylation changes in the amnion may be at least partially involved in the physiological process of labor and the etiology of preterm birth and suggests that DNA methylation profiles, in combination with other biological data, may provide valuable insight into the mechanisms underlying normal and pathological pregnancies.
    The Scientific World Journal 02/2013; 2013(4):678156. DOI:10.1155/2013/678156 · 1.73 Impact Factor
  • Source
    • "Recent studies have shown that the carriers of polymorphic alleles of TLR4 (Toll-like receptor 4), which plays a fundamental role in pathogen recognition and activation of innate immunity, are at increased risk of pPROM and subsequent PD [24]. It has also been revealed that the carriage of polymorphic alleles encoding for MMP1 (matrix metalloproteinase 1), a protein involved in the breakdown of extracellular matrix, influences the risk of pPROM [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our previous study revealed that anti-inflammatory cytokine gene polymorphisms increase the risk of spontaneous preterm delivery (PD) in a population of Polish women. Different genetic background of PD due to preterm premature rupture of membranes (pPROM) than PD without pPROM has been suggested. The aim of this study was to examine the relationship between the maternal carriage of polymorphic alleles of the following genes: interleukin 1β(IL-1β [+3953C>T]), interleukin 6 promoter (IL-6 [-174G>C]), tumour necrosis factor promoter (TNF-α [-308G>A]) and interleukin 1 receptor antagonist (IL-1RN) and the risk of PD caused exclusively by pPROM in a population of Polish women. A case-control study. 95 Caucasian women were examined including 32 cases and 63 controls. Case subjects experienced a delivery at less than 36 weeks and 6 days of gestation due exclusively to pPROM while control subjects gave birth at term. Polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). NO STATISTICALLY SIGNIFICANT RELATIONSHIP BETWEEN POLYMORPHISMS OF EXAMINED GENES AND RISK OF PD DUE TO PPROM IN A POPULATION OF POLISH WOMEN WAS FOUND: OR = 0.84 (95% CI: 0.34-2.01) for IL-1β, OR = 0.77 (95% CI: 0.27-2.13) for IL-6, OR = 0.72 (95% CI: 0.26-1.90) for TNF-α and OR = 1.74 (95% CI: 0.66-4.64) for IL-1RN. Maternal carriage of polymorphic alleles of IL-1β, IL-6 promoter, TNF-α promoter and IL-1RA seems to have no impact on the risk of PD due to pPROM in the population of Polish women.The genetic contribution and pathomechanism of PD related to pPROM seems to differ from those of spontaneous PD without pPROM.
    08/2010; 6(4):552-7. DOI:10.5114/aoms.2010.14467
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ethnic disparity in preterm delivery between African Americans and European Americans has existed for decades, and is likely the consequence of multiple factors, including socioeconomic status, environment, and genetics. This review summarizes existing information on genetic variation and its association with preterm birth in African Americans. Candidate gene-based association studies, in which investigators have evaluated particular genes selected primarily because of their potential roles in the process of normal and pathologic parturition, provide evidence that genetic contributions from both mother and fetus account for some of the disparity in preterm births. To date, most attention has been focused on genetic variation in pro- and anti-inflammatory cytokine genes and their respective receptors. These genes, particularly the pro-inflammatory cytokine genes and their receptors, are linked to matrix metabolism because these cytokines increase expression of matrix degrading metalloproteinases. However, the role that genetic variants that are different between populations play in preterm birth (e.g. the SERPINH1 - G56 SNP) cannot yet be quantified. Future studies based on genome wide association or admixture mapping may reveal other genes that contribute to disparity in prematurity.
    Pediatric Research 09/2008; 65(1):1-9. DOI:10.1203/PDR.0b013e31818912e7 · 2.31 Impact Factor
Show more