Identifying unique regulatory elements related to polymorphic imprinting and gestational aging in the placenta

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In this application we propose a series of experiments to better understand the hierarchical placental epigenome across gestation (by assessing two different developmental time points) to determine intra-sample variability and to gain widespread functional insights of potential cis-acting regulatory elements with unique placenta profiles. The data will be generated and assessed in a genome-wide unbiased fashion, allowing us to monitor gestational-dynamics in imprinted gene expression and identify cis-regulatory usage that would account for the widespread down-regulation of expression previously reported.

There is an inter-relationship between DNA methylation and additional layers of epigenetic information essential for genome function. We have previously shown that the placenta is uniquely hypomethylated and that this methylation is dynamic through pregnancy. However, addition epigenetic tiers have largely been uncharacterised in this essential tissue and mechanisms responsible for the global increase in methylation (on the unique hypomethylated background) are unknown. Fascinatingly, transcriptional down-regulation associated with imprinted transcripts at term is independent of methylation, since all imprinted differentially methylated regions maintain faithful allelic profiles, suggesting other epigenetic mechanisms must be responsible.

Main deliverables: (1) We will produced consensus epigenetic maps for early and late placenta samples. Through exploitation of these datasets, we will ultimately identify functional regulatory elements, many of which we anticipate will change during gestation. (2) By performing bioinformatic analyses using trio-SNP information to discriminate alleles, the temporal epigenetic and expression profiles for imprinted genes will be revealed. Since the epigenetic datasets will be produced in an unbiased genome-wide fashion, this will allow novel cis-regulatory elements to be defined and functionally characterised.