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.

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    • "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, "
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    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.
    Full-text · Article · Feb 2013 · The Scientific World Journal
    • "), de l'accentuation de l'apoptose[8,9,36]et d'un déséquilibre entre la production et la dégradation de la MEC (augmentation de MMP8 et MMP9, diminution de TIMP1 et TIMP3[17,19,37]). Au-delà de l'influence de l'organisme maternel, la modification du statut épigénétique des cellules de l'amnios et du chorion pourrait également influencer l'expression des MMP ou des prostaglandines[38,39]. La survenue d'une rupture au décours d'un geste invasif (rupture iatrogène) ne répond pas strictement aux même mécanismes. "
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    ABSTRACT: Rupture of membranes (ROM) depends on mechanical stretch, extracellular matrix components imbalance and increased apoptosis. It occurs in 2 to 3% of all pregnancies before 37weeks' gestation (WG) and in up to 10% at term. Main consequences are labor induction and risk of maternal-fetal infection. ROM is associated with one third of preterm births and about 20% of perinatal mortality. This review deals with recent knowledge concerning ROM including diagnosis and management. In many cases, ROM is easily identified by clinical examination. In other cases, the use of vaginal pH appears to be less efficient than the use of immunochromatographic strips based on IGFBP-1 or PAMG-1 detection. Before 34WG, conservative management consists in in utero transfer, antibioprophylaxis and corticosteroids. After 37WG, delivery is the most appropriate option. Between 34 and 37WG, recent studies demonstrate that induction of labour does not improve pregnancy outcomes. Therefore, expectant management can be the first option between 34 and 37WG when no active infection is suspected especially in case of unfavourable cervix.
    No preview · Article · Feb 2013 · Journal de Gynécologie Obstétrique et Biologie de la Reproduction
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    • "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]. "
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    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.
    Full-text · Article · Aug 2010
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