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Human Molecular Genetics Advance Access published online on January 4, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddm381
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Hongyan Wang1,{ddagger}, Masaki Ogawa2,{ddagger}, Jennifer R. Wood2, Marisa S. Bartolomei3, Mary D. Sammel4, Juan Pedro Kusanovic5, Scott W. Walsh6, Roberto Romero5 and Jerome F. Strauss, III6,*

1 State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University School of Life Science, Shanghai, China 200433 2 Center for Research on Reproduction & Women's Health, University of Pennsylvania, Philadelphia, PA 19104 3 Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 4 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, 19104 5 Perinatology Research Branch, NICHD, Hutzel Hospital, Detroit, MI, 48201 6 Department of Obstetrics & Gynecology, Virginia Commonwealth University, Richmond, VA, 23298

* Corresponding author: Jerome F. Strauss III, M.D., Ph.D. Virginia Commonwealth University MCV Campus, Sanger Hall, 1st Floor, Room 1-071, 1101 East Marshall Street, P.O. Box 980565, Richmond, Virginia 23298. Tel: 804-828-9788, Fax: 804-828-7628 email: jfstrauss{at}vcu.edu

Received November 26, 2007; Revised December 20, 2007; Accepted December 20, 2007

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. 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 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.

{ddagger} These authors contributed equally to this work.


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