Bioinformatic Approaches to Analysing RRBS Data in the Context of Pre-eclampsia
Roberts, Hester Emily

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Roberts, H. E. (2015). Bioinformatic Approaches to Analysing RRBS Data in the Context of Pre-eclampsia (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/5831
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http://hdl.handle.net/10523/5831
Abstract:
The placenta is a crucial element of human life. It sustains and enables the development from a small group of cells to a whole organism. The placenta is a unique organ that fulfils multiple roles, from delivery of oxygen and nutrients, to removal of waste products. During embryo implantation, the trophoblast cells on the outside of the blastula invade the maternal endometrium and contact maternal spiral arteries. These trophoblast cells extensively remodel the maternal spiral arteries, establishing a blood supply to the growing embryo. On occasion, elements of this process malfunction, resulting in placental pathology. Pre-eclampsia is a serious and unfortunately common disease that arises only during pregnancy. The main clinical hallmarks of pre-eclampsia are the new onset of maternal hypertension, and proteinuria. These symptoms arise only in the second half of pregnancy, but the pathogenesis lies much earlier in pregnancy. Pre-eclamptic placentas display reduced invasion of the trophoblast, and restriction of maternal spiral arteries, in turn restricting blood flow to the fetus, and causing a hypoxic state.Epigenetic modifications in the placenta are distinct from those in any somatic tissue. Hypomethylation across the genome, and in particular at promoter regions, imprinted genes, and repetitive regions within the genome of placental cells appears to play a crucial role in the development of the placenta. Therefore, I have hypothesised that alterations to the methylation of placental cells may contribute to aberrant placentation. This thesis demonstrates the first use of Reduced Representation Bisulphite Sequencing to investigate genome-wide DNA methylation in pre-eclampsia/toxaemia. In the course of this investigation, significant progress has been achieved in our understanding of data from Reduced Representation Bisulphite Sequencing, contributing to the bioinformatic and biostatistic pipeline for the analysis of this data. A large number of CpG sites have been identified in a matched cohort of pre-eclamptic placentas to show differential methylation when compared to a cohort of control placentas. The majority of these sites display hypomethylation in pre-eclamptic placentas, and globally, CpG sites from pre-eclamptic placentas show 2% less methylation than their control counterparts.In addition, an investigation has been undertaken into the methylation status of two genes that have shown evidence of differential methylation. This particular study was undertaken in human blood to establish a baseline of normal methylation in a normal, accessible, and well phenotypes tissue. These results will contribute towards our understanding of DNA methylation in both normal and diseased states, with particular emphasis on the role that methylation plays in placental development.
Date:
2015
Advisor:
Morison, Ian M; Macaulay, Erin C; Hung, Noelyn A
Degree Name:
Doctor of Philosophy
Degree Discipline:
Pathology
Publisher:
University of Otago
Keywords:
Pre-eclampsia; Epigenetics; RRBS; Bioinformatics
Research Type:
Thesis
Languages:
English
Collections
- Thesis - Doctoral [2734]
- Pathology collection - Dunedin [65]