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Imprinted genes in the placenta and obstetrical complications

University of British Columbia

Each year, many pregnancies are associated with obstetrical complications such as maternal pre-eclampsia (PET) and fetal intrauterine growth restriction (IUGR). Poor placentation is thought to contribute to these complications, but specific causes are largely unknown. Mouse models suggest that epigenetic mechanisms, in particular genomic imprinting, that alter gene regulation may help regulate placental development and embryonic growth. The first goal of this thesis is to examine if epigenetic modifications (i.e. DNA methylation) and altered expression of imprinted genes in the human placenta are contributing factors to PET and IUGR. The second goal of this thesis is to identify imprinted loci that are useful in the diagnosis of placental pathologies that associated with abnormal imprinting, including triploidy, hydatidiform moles, and placental mesenchymal dysplasia. I found that DNA methylation at the imprinting control region 1 (ICR1) on chromosome 11p15.5 was significantly decreased in IUGR placentas (p < 0.001), but not in those associated with pre-eclampsia. Methylation at ICR2 (KvDMR1) was not significantly altered in PET or IUGR. No significant changes in expression levels were observed in the genes controlled by these ICRs. There were no significant methylation changes observed in any candidate imprinted gene evaluated by the Illumina array. LINE-1 methylation, a marker of whole genome methylation, was also similar in all groups. The establishment of biomarkers that could be used to accurately identify those women at an increased risk for pre-eclampsia or IUGR would be a major step forward in antenatal care. All placental pathologies (triploidy, hydatidiform moles or placental mesenchymal dysplasia) were associated with altered ICR2 (KvDMR1) methylation. Pyrosequencing assays for SGCE, SNRPN, and MEST were also compared for their utility in diagnosing parental genomic imbalance in placental samples. SGCE showed the clearest separation between groups. The combined use of KvDMR1 and SGCE assays could provide a potentially valuable diagnostic tool in the rapid screening of methylation errors in placental disorders. These results also demonstrate the maintenance of imprinting status at these loci in the human placenta, even in the presence of abnormal pathology.

Text

2010-06-08

Attribution-NonCommercial-NoDerivs 3.0 Unported

http://hdl.handle.net/2429/25509

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/3.0/