An integrative analysis of the human placental transcriptome

Abstract

Pregnancy outcome is inextricably linked to placental development, which is strictly regulated both temporally and spatially by mechanisms that are only partially understood. Although the placenta is absolutely indispensable for fetal development in utero, it remains the least understood human tissue. Although the placenta is a shared organ between the mother and fetus, it is of embryonic origin, and therefore its development is largely regulated by the fetal genome. This overall goal of this research was to investigate three key aspects of human placental gene regulation: (1) The effect of genomic imprinting on gene regulation, (2) the differences in placental gene expression between the sexes, and (3) the co-expression relationships that exist between genes on a transcriptome scale. Firstly, this research identified a window of epigenetic imprinting plasticity for the long non-coding RNA H19, which is heavily implicated in placental development and function. These results suggested that variation in H19 imprinting may contribute to early programming of placental phenotype and highlighted the need for quantitative and robust methodologies to further elucidate the role of imprinted genes in normal and pathological placental development. Secondly, by conducting a transcriptome-scale meta-analysis of sex-biased gene expression, this research revealed that 140 genes are differentially expressed between male and female placentae. A majority of these genes are autosomal, many of which are involved in high-level regulatory processes such as gene transcription, cell growth and proliferation and hormonal function. Of particular interest, all genes in the LHB-CGB cluster were expressed more highly in female placentas, which includes genes involved in placental development, the maintenance of pregnancy and maternal immune tolerance of the conceptus. These results demonstrated that sex-biased gene expression in the normal human placenta occurs across the genome and includes genes that are central to growth, development and the maintenance of pregnancy. Thirdly, by undertaking a comprehensive analysis of human placental gene co-expression using RNA sequencing and the integration of five human and one mouse transcriptome dataset, this research identified clusters of correlated genes, whose patterns of co-expression are highly preserved across human gestation and between human and mouse, subsequently revealing highly conserved molecular networks involved in placental development. Furthermore, by reducing the complexity of the placental transcriptome by summarizing co-expressed genes, this work identified a group of co-expressed genes implicated in preeclampsia and also outlines a novel method for identifying for non-invasive biomarkers of placental development. In summary, each aspect of this PhD research has provided new insights into how gene expression is regulated in the human placenta and has revealed previously unappreciated aspects of the placental transcriptional landscape.