Pregnancy Loss: Genomic Imprinting of X-Inactivation

Magee-Women'S Res Inst And Foundation, Pittsburgh PA

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Abstract

There is a wealth of information on known or suspected genetic and environmental causes of adverse pregnancy outcomes in women. In addition to these causes, there is now increasing suspicion that defects in epigenetic inheritance are a significant source of many adverse pregnancy outcomes. In this project, the effects of disruptions in normal epigenetic inheritance on pregnancy outcome will be studied, primarily using non-invasive magnetic resonance microscopy (MRM) imaging of in utero mouse fetal development. Germline epigenetic inheritance, or genomic imprinting, is disrupted in a strain of mice carrying a maternal effect mutation in the Dnmtl (cytosine-5) methyltransferase gene. Heterozygous mutant embryos derived from homozygous mutant females die at different times throughout gestation because of an inability to maintain methylation patterns on imprinted genes. In Specific Aim 1, the developmental course of these heterozygous mutant embryos and their placentae will be assessed by sequential MRM imaging. In Specific Aim 2, diploid-tetraploid chimeric embryos will be produced from wild-type and Dnmtl mutant embryos in order to study the course of fetal development in mice with imprinting defects confined to embryonic or extraembryonic tissues. Compared to the mice studied in Specific Aim 1, these mice will most likely represent a unique spectrum of adverse pregnancy outcomes. In Specific Aim 3, the effects of abnormalities in epigenetic inheritance will be studied by assessing the fetal development of male and female embryos that inherit the recessive X-linked lethal mutations tortoiseshell and bare patches. X-chromosome inactivation will be studied in these mice, as they are potential models for women with skewed X inactivation, which has been recently recognized to be associated with a high incidence of recurrent spontaneous abortion in women. Overall, the goal of this research is to better understand the effects of disruptions in normal germline and somatic epigentic inheritance on fetal development and pregnancy outcome.