For most human genes, maternal and paternal alleles are bi-allelically expressed. However, a specific subset of genes are imprinted and mono-allelically expressed. The current dogma is that this embryonic imprint is stable across the lifespan of the organism. Loss of imprinting (LOI) leads to bi-allelic expression of the imprinted gene, potentially causing a doubling of gene dosage or gene dysregulation, resulting in disease. Because the methylation marks of imprinted genes are considered permanent after fertilization, any acquired changes in the intrauterine environment may lead to stable transgenerational effects. The regulatory complexity of these imprinted gene domains may render them particularly sensitive to environmental changes such as diet and nutrition. Emerging evidence implicates aberrant imprinting in the pathophysiology of many common human diseases, including complications of pregnancy such as intrauterine growth restriction (IUGR) and preeclampsia (PE);and even postnatal disorders such as obesity, cardiovascular disease, and type 2 diabetes. We have developed a highly sensitive and quantitative allele-specific PCR analysis to measure LOI in a panel of imprinted genes in the human genome. Using this methodology, we have already determined that pregnancies complicated by PE and IUGR are associated with dysregulation of a set of imprinted genes in the placenta. Both of these obstetrical disorders have their origins in an early intrauterine environment associated with aberrant placentation and trophoblast invasion. We also have novel evidence to suggest that genomic imprinting patterns are not permanently fixed in placental development. Contrary to the prevailing theory, we hypothesize that patterns of LOI are not static in the human placenta and are subject to developmental and environmental influences over the course of pregnancy that predispose to adverse pregnancy outcome. We now propose a longitudinal trial as a secondary study to the NuMOM2B Trial to monitor LOI in placenta samples from first trimester CVS to birth and determine which LOI patterns in the first trimester lead to normal pregnancy outcomes and which patterns are predictive of pregnancy complications.
We have novel preliminary data to suggest that genomic imprinting in the human placenta takes place across gestation and is not permanently fixed in early pregnancy. We seek to confirm this finding in a longitudinal study of loss of imprinting by monitoring placenta samples from chorionic villus sampling in the first trimester and the same respective placentas at birth. We will also explore how differences in loss of imprinting patterns in first trimester placenta samples may be predictive of pregnancy complications which can ultimately be developed into a bioassay for adverse pregnancy outcomes.
