Fetal growth potential reflects a complex regulatory system delivered by genetic and environmental factors acting directly on the fetus or through the placenta. Compromise of this potential, as seen in intrauterine growth restriction (IUGR), is associated with increased perinatal mortality and short and long term morbidity. The expression of several genes has been shown to be disturbed in placentas of fetuses with growth restriction. However, the primary causes for these changes have not yet been elucidated.
I proposed that epigenetic mechanisms, specifically DNA methylation, may be involved in placental development leading to modulation of the expression of specific genes, and that their altered regulation will impact fetal development and growth.
My primary objective was to identify DNA methylation variation in placenta, in association with variation of gene expression and with poor fetal growth.
I used a global genomic screening approach, with 24 selected placental samples, from newborns considered IUGR or normal controls, to identify candidate target genomic regions carrying epigenetic alterations. Candidate regions were followed up, by expression analysis of corresponding regulated genes, for associations with altered expression and by targeted methylation analysis in an expanded cohort of 170 samples, for associations with birthweight percentile. I analyzed methylation variation at imprinting centers (IC), gene promoters and CpG islands.
In two genome-wide case control screening studies using distinct commercial microarray platforms I identified approximately 68 differentially methylated autosomal candidate genomic regions overlapping gene promoters. Hypomethylated CpGs mapping to gene promoters were found to be more abundant in placentas of growth restricted newborns than in controls. One of the most interesting candidates, WNT2, was analyzed in an extended sample cohort and showed an association of high promoter methylation to low expression as well as low birthweight percentile. This gene is involved in a pathway that diverts cells from programmed apoptosis. It is highly expressed in placenta, and in mice, targeted biallelic inactivation of Wnt2 has been shown to cause poor growth and perinatal death in 50% of the affected pups.
These findings support the hypothesis that dysregulation of epigenetic mechanisms are involved in abnormal placental development and can impact fetal growth.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/31901 |
| Date | 11 January 2012 |
| Creators | Pinto Barreto Ferreira, Jose Carlos |
| Contributors | Weksberg, Rosanna |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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