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

Hongyan Wang, Masaki Ogawa, Jennifer R Wood, Marisa S. Bartolomei, Mary D. Sammel, Juan Pedro Kusanovic, Scott W. Walsh, Roberto Romero, Jerome F. Strauss

Research output: Contribution to journalArticle

47 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1087-1096
Number of pages10
JournalHuman Molecular Genetics
Volume17
Issue number8
DOIs
StatePublished - Apr 15 2008

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Matrix Metalloproteinase 1
Epigenomics
Amnion
DNA Methylation
Extraembryonic Membranes
Fibroblasts
Alleles
decitabine
Single Nucleotide Polymorphism
Rupture
Fibrillar Collagens
Preterm Premature Rupture of the Membranes
Chromatin Immunoprecipitation
Nuclear Proteins
Extracellular Matrix
Transfection
Case-Control Studies
Plasmids
Parturition
Membranes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes. / Wang, Hongyan; Ogawa, Masaki; Wood, Jennifer R; Bartolomei, Marisa S.; Sammel, Mary D.; Kusanovic, Juan Pedro; Walsh, Scott W.; Romero, Roberto; Strauss, Jerome F.

In: Human Molecular Genetics, Vol. 17, No. 8, 15.04.2008, p. 1087-1096.

Research output: Contribution to journalArticle

Wang, H, Ogawa, M, Wood, JR, Bartolomei, MS, Sammel, MD, Kusanovic, JP, Walsh, SW, Romero, R & Strauss, JF 2008, 'Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes', Human Molecular Genetics, vol. 17, no. 8, pp. 1087-1096. https://doi.org/10.1093/hmg/ddm381
Wang, Hongyan ; Ogawa, Masaki ; Wood, Jennifer R ; Bartolomei, Marisa S. ; Sammel, Mary D. ; Kusanovic, Juan Pedro ; Walsh, Scott W. ; Romero, Roberto ; Strauss, Jerome F. / Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 8. pp. 1087-1096.
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