Article

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: 6.68). 04/2008; 17(8):1087-96. DOI: 10.1093/hmg/ddm381
Source: PubMed

ABSTRACT 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

Full-text

Available from: Jennifer R Wood, Jul 06, 2015
0 Followers
 · 
96 Views
  • Source
    [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; 2013:678156. DOI:10.1155/2013/678156 · 1.73 Impact Factor
  • 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 · 2.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prenatal stress is associated with an increased vulnerability to neurodevelopmental disorders, including autism and schizophrenia. To determine the critical time window when fetal antecedents may induce a disease predisposition, we examined behavioral responses in offspring exposed to stress during early, mid, and late gestation. We found that male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity, anhedonia, and an increased sensitivity to selective serotonin reuptake inhibitor treatment. Long-term alterations in central corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, as well as increased hypothalamic-pituitary-adrenal (HPA) axis responsivity, were present in these mice and likely contributed to an elevated stress sensitivity. Changes in CRF and GR gene methylation correlated with altered gene expression, providing important evidence of epigenetic programming during early prenatal stress. In addition, we found the core mechanism underlying male vulnerability may involve sex-specific placenta responsivity, where stress early in pregnancy significantly increased expression of PPARalpha (peroxisome proliferator-activated receptor alpha), IGFBP-1 (insulin-like growth factor binding protein 1), HIF3alpha (hypoxia-inducible factor 3a), and GLUT4 (glucose transporter 4) in male placentas but not females. Examination of placental epigenetic machinery revealed basal sex differences, providing further evidence that sex-specific programming begins very early in pregnancy, and may contribute to the timing and vulnerability of the developing fetus to maternal perturbations. Overall, these results indicate that stress experience early in pregnancy may contribute to male neurodevelopmental disorders through impacts on placental function and fetal development.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 10/2008; 28(36):9055-65. DOI:10.1523/JNEUROSCI.1424-08.2008 · 6.75 Impact Factor