We have been a bit quiet recently, but have nonetheless been keeping busy! 2021 has brought some exciting advancements, including two new publications from the lab. Both of these projects have been the result of a few years and a lot of work by both lab members and collaborators.
Giulia Del Gobbo (PhD student) had a manuscript published in Molecular Medicine “Genomic imbalances in the placenta are associated with poor fetal growth”[ https://molmed.biomedcentral.com/articles/10.1186/s10020-020-00253-4 ]. This project was very exciting for us, as it allowed us to go back to some of our roots studying confined placental mosaicism and collaborate with former PhD student Ryan Yuen, who is now an Assistant Professor with his own research program at the University of Toronto and Hospital for Sick Children! Here is a quick summary:
When the placenta does not function efficiently, babies may be growth-restricted, which can poorly impact their health. From our past research, we know that a cause of poor placental function and fetal growth restriction is trisomy (extra chromosome) in the placenta but not the baby (confined placental mosaicism), however many cases of fetal growth restriction are still unexplained. In this study, we sought to test whether imbalances of smaller sections of the chromosomes, copy number variants (CNVs) that delete or duplicate sections of a chromosome, are also associated with poor fetal growth, as this had not yet been properly tested. First, we tested for whole chromosomal errors and confined placental mosaicism in a cohort of babies born too small and normally-grown controls. We found that trisomy or partial trisomy was ten times more frequent in placentas from small babies compared to those from normally-grown babies, and all of these were confined to the placenta. In placentas without large chromosome errors, we investigated CNVs, and found that there was no difference in the total number or amount of DNA that was affected by CNVs between small and normally-grown babies. However, in nearly 6% of the placentas from small babies, we found CNVs that are rare in the population and that affect genes that are involved in placental function or fetal growth that might explain the poor growth in these cases. This helps to shed light on how CNVs in the placenta may also impact placental function and therefore fetal growth, and provides a foundation for future research in this field.
Victor Yuan (PhD student) published in BMC Genomics “Cell-specific characterization of the placental methylome” [https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-020-07186-6] . This project was a huge team effort between Wendy’s and Alex Beristain’s labs! Alex brought his expertise in placental cell types to help isolate 4 major cell types from first trimester and term placentas, samples which were then profiled for DNA methylation and analyzed by Victor and the rest of the team. Here is a short summary of the work:
Studying DNA methylation in the placenta provides useful insight into its function in development and role in health/disease. However, sampling of whole tissue (chorionic villi) obscures the story happening at the level of the constituent cell types. We profiled DNA methylation using the Illumina EPIC array from four major placental cell types and found that they are really different from each other! Trophoblast cells are strange and exotic, while Hofbauer cells (placental macrophages) look like they have migrated there from another land. We found tens to hundreds of thousands of differentially methylated CpGs per cell type. Many of these were in genes with already well-characterized function, but many other genes with less clear relevance were also identified. We looked specifically at some unique epigenetic features: imprinting, partially methylated domains, and repetitive elements. We found that most were conserved in Trophoblasts, but for other cell types, the story is more complicated (interesting!). Lastly, with DNA methylation profiles for major cell types available, we can now apply reference-based cell deconvolution in whole placental villi studies, which Victor has developed into an R package planet. Overall, this study emphasizes the high cell-specificity of DNA methylation in placental development and function. It demonstrates the importance of considering cell specificity in future placental studies.