Genetic Regulation of Transcription in the Endometrium in Health and Disease.

The endometrium is a complex and dynamic tissue essential for fertility and implicated in many reproductive disorders. The tissue consists of glandular epithelium and vascularised stroma and is unique because it is constantly shed and regrown with each menstrual cycle, generating up to 10 mm of new mucosa. Consequently, there are marked changes in cell composition and gene expression across the menstrual cycle. Recent evidence shows expression of many genes is influenced by genetic variation between individuals. We and others have reported evidence for genetic effects on hundreds of genes in endometrium. The genetic factors influencing endometrial gene expression are highly correlated with the genetic effects on expression in other reproductive (e.g., in uterus and ovary) and digestive tissues (e.g., salivary gland and stomach), supporting a shared genetic regulation of gene expression in biologically similar tissues. There is also increasing evidence for cell specific genetic effects for some genes. Sample size for studies in endometrium are modest and results from the larger studies of gene expression in blood report genetic effects for a much higher proportion of genes than currently reported for endometrium. There is also emerging evidence for the importance of genetic variation on RNA splicing. Gene mapping studies for common disease, including diseases associated with endometrium, show most variation maps to intergenic regulatory regions. It is likely that genetic risk factors for disease function through modifying the program of cell specific gene expression. The emerging evidence from our gene mapping studies coupled with tissue specific studies, and the GTEx, eQTLGen and EpiMap projects, show we need to expand our understanding of the complex regulation of gene expression. These data also help to link disease genetic risk factors to specific target genes. Combining our data on genetic regulation of gene expression in endometrium, and cell types within the endometrium with gene mapping data for endometriosis and related diseases is beginning to uncover the specific genes and pathways responsible for increased risk of these diseases.