human placental-specific epipolymorphism and its association with adverse pregnancy outcomes人类placental-specific epipolymorphism及其与不良妊娠结局的关联.pdfVIP

Human Placental-Specific Epipolymorphism and its Association with Adverse Pregnancy Outcomes 1 1 ˜ 1 2 1 Ryan K. C. Yuen , Luana Avila , Maria S. Penaherrera , Peter von Dadelszen , Louis Lefebvre , Michael S. 1 1 Kobor , Wendy P. Robinson * 1 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada, 2 Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, British Columbia, Canada Abstract Interindividual variation in DNA-methylation level is widespread in the human genome, despite its critical role in regulating gene expression. The nature of this variation, including its tissue-specific nature, and the role it may play in human phenotypic variation and disease is still poorly characterized. The placenta plays a critical role in regulating fetal growth and development in ways that have lifelong effects on health. To identify genes with a high degree of interindividual DNA methylation variation in the human placenta, we surveyed the human genome using the Illumina GoldenGate Methylation Cancer panel targeting 1505 CpG sites of 807 genes. While many sites show a continuous pattern of methylation levels, WNT2, TUSC3 and EPHB4 were identified to have a polymorphic ‘‘on-or-off’’ pattern of DNA methylation variation at their promoter region which was confirmed by pyrosequencing. Methylation of these genes can be found in 7%–25% of over 100 placentas tested. The methylation state at the promoter of these genes is concordant with mRNA allelic expression. In three informative cases TUSC3 was observed to be methylated on the maternal allele, and it is thus possible this represents a polymorphically im