Erin C. Macaulay, Hester E. Roberts, Noelyn A. Hung, Ian M. Morison
Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin
Pre-eclampsia is a potentially dangerous condition of pregnancy that is associated with abnormal placental development. Unfortunately, the condition is commonly undetected until after the 24th week of gestation, by which time it can already pose a threat to both mother and infant. Recent work suggests that epigenetics may play a critical role in the onset, severity and potential heritability of pre-eclampsia. The goal of this project is to determine the epigenetic contribution to pre-eclampsia in order to identify biologically meaningful epigenetic markers that may be used clinically for the early detection and/or prevention of this placental disease.
The human placenta is known to be globally hypomethylated in comparison to somatic fetal tissues. We previously found that retrotransposons in the normal placenta show particularly low methylation. Since retrotransposons are usually silenced by methylation in somatic tissues (to maintain genome stability), we hypothesized that their placental expression may have a bearing on the development of placental dysfunctions. We examined the methylation of several retrotransposon-derived promoters using Sequenom MassARRAY and found that placental hypomethylation appears to be critical for normal placental function; thus aberrant methylation may alter placental function and lead to pre-eclampsia.
We are currently using reduced-representation bisulfite sequencing (RRBS) to sequence the methylome in pre-eclampsia. RRBS quantifies the methylation of 4 million CpG sites across the genome. We have sequenced a matched case-control cohort consisting of 15 pre-eclamptic and 15 control placentas, and are applying large-scale methylation analysis tools to generate a ranked list of epigenetic differences to identify candidate differentially-methylated genes. We will then perform high-throughput RNA-sequencing to define the transcriptome in pre-eclapmsia. By comparing the methylome with the transcriptome, we will be able to determine which of the differentially methylated genes and gene regions show biologically meaningful differences in gene expression in pre-eclampsia.