Robinson Lab

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.

In September 2016 the International Federation of Placenta Assocations (IFPA) meeting was in lovely Portland, Oregon. To prepare for the meeting, the lab (in part) plus collaborator Alex B. hit the mountain trails in Central Oregon. What could be more inspiring than breathing in the mountain air, listening to some folk music in nearby Sisters and enjoying dinners in the forest?

Clearly our prep work was successful as Sam Wilson won the Elsevier Trophoblast Research New Investigator Award for the best Poster Presentation by a New Investigator at the IFPA meeting and is now invited to give an oral presentation at next years meeting in Manchester England!

Great time kayaking out in False Creek in late Spring 2016! Poured rain and a bit cold at the end, but nothing the pub couldn’t cure after.

The event celebrated the graduation of Magda P. (PhD, studying DNAm and Neural Tube Defects)and Olivia de G. (MSc studying DNAm in cord blood cells from preterm and term births and moving on to doctoral studies at Stanford). It also marked the end of Laeticia L’s productive visit to our lab investigating the effects of maternal depression on DNA  methylation.

Lab cheers their fellow grad student Olivia (goalie) of the UBC Thunderbirds en route to winning the CIS championship!

Magda showing the same grace and strength on the wall as in the lab. Alex B. pondering which 5.12 he should climb next. Kirsten showing concern?

Everyone shows their willingness to be adventurous and push themselves higher in our Lab climbing outing in December (2013).

John’s Master degree work on DNA methylation changes in preeclampsia has come out in two publications. The first study demonstrates how many changes in DNA methylation there are in placentas with preeclampsia—Thousands! So many its hard to know what to say except –wow! How does the placenta support the baby at all when so much has changed? Of course, such placentas tend to show obvious pathology and what we are seeing may be a reflection of that altered cellular composition and behaviour–but the placenta is so complex, it is difficult to sort out what is really going on. Regardless of the why, we think this could be very useful for identifying new clinical markers of preeclampsia, as well as understanding how the placenta adapts and changes to different situations.

• Widespread DNA hypomethylation at gene enhancer regions in placentas associated with early-onset pre-eclampsia. Blair JD, Yuen RK, Lim BK, McFadden DE, von Dadelszen P, Robinson WP. Mol Hum Reprod. 2013 Oct;19(10):697-708.

This second follow-up paper was fun as we were able to connect our newer work on preeclampsia with our older work on confined placental mosaicism (CPM). Paul Yong (former PhD student) had published back in 2006 that pregnancies associated with CPM for trisomy 16 were at high risk of preeclampsia. So we decided to go back and compare methylation changes in these placentas with those from chromosomally normal preeclampsia. Many similarities were found, though as expected, CPM16 had even more methylation changes! These changes seem largely to arise later in development rather than being set in the first trimester.

• Overlapping DNA methylation profile between placentas with trisomy 16 and early-onset preeclampsia. Blair JD, Langlois S, McFadden DE, Robinson WP. Placenta. 2014 Mar;35(3):216-22.

First of all congratulations to Courtney Hanna who completed her PhD late last spring and moved on to an exciting postdoctoral fellowship at the Babraham Institute in Cambridge, England. Also to John Blair who completed his Masters last summer and moved on to my former Alma Mater (UC Berkeley) and is now enjoying all the great food and exciting life there (when he finds time to escape the lab that is!). We miss them both! Likewise, Kirsten Hogg has just completed her postdoctoral fellowship here and is moving down under to another postdoctoral position in Melbourne! Time goes by so fast..sigh.

We do have two new graduate student who have joined the lab in this last year: Sam Wilson and Olivia de Goede. They have big shoes to fill but have started off with good strides.

Hello Everyone.  Here is our 2013 Summer newsletter.  Please let us know if you have any questions.

The lab has been busy in the fall and winter with a number of new publications:

Kirsten Hogg (Postdoc) had a paper published in Mol Cell Endocrinol. on “Hypomethylation of the LEP gene in placenta and elevated maternal leptin concentration in early onset pre-eclampsia.” Increased levels of a hormone called leptin are found in the blood of women with pre-eclampsia. Leptin, which is produced by our fat cells and regulates appetite, is also made in the placenta and is very important for cell growth, nutrient supply to the fetus and regulation of hormones. In this study, we looked at how changes in DNA methylation could explain differences in leptin expression in pre-eclampsia. In the placenta, DNA methylation was lower at the leptin gene in patients with early onset pre-eclampsia, the most severe form, but not changed in late onset pre-eclampsia, a milder form.  Also, DNA methylation did not differ in placentas from babies that were underweight, but pre-eclampsia was absent in the mother. These results help to explain the corresponding increase in leptin in maternal blood in pre-eclampsia. Many other changes in gene DNA methylation are expected to occur in pre-eclampsia and are important to study to better understand this placental condition and help to provide targeted preventative intervention.

Ryan Yuen (who completed his PhD last year in the lab) had a manuscript published in Epigenetics “Hypoxia alters the epigenetic profile in cultured human placental trophoblasts.” This was a joint project with Dr. Mike Nelson’s lab in St Louis. Both preeclampsia and low birthweight are caused in part by placentas that develop poorly as a result of insufficient blood flow from the mother to the placenta. This low blood flow can cause low levels of oxygen at the placental surface. While low-oxygen is normal in the first trimester of development, insufficient oxygen in the second trimester can cause various changes in the placenta and lead it to express proteins that can affect the mothers blood pressure. To study what happens when there is insufficient oxygen, trophoblast cells (the placental cells directly in contact with mother’s blood) were cultured under three different oxygen levels,<1%, 8% and 20%. We found that a small subset of genes showed an increase of DNA methylation when cultured in hypoxic (<1%) oxygen conditions. Many of the specific sites that changed were places where another protein, AP-1, binds to the DNA. We also found that the components of this protein showed increased expression in the cells cultured under low oxygen. We suggest that AP-1 causes DNA methylation to accumulate at the sites that it binds shutting down the associated genes and causing the cells to change their growth direction. Understand the early steps in the process leading to abnormal placentation may lead to novel therapies to reduce their occurrence.

Magda Price (PhD student) published a paper in Epigenetics Chromatin entitled: Additional annotation enhances potential for biologically-relevant analysis of the Illumina Infinium HumanMethylation450 BeadChip array.  This was a joint project with the Kobor and Brown labs at UBC.  Measurement of genome-wide DNA methylation (DNAm) using the Illumina 450K array is increasingly used to characterize epigenetic changes in the human genome in association with disease, development and aging, or environmental exposures. However, some of the over 485,000 probes may give misleading results. It is important to identify and eliminate troublesome probes before performing statistical analysis of the data. Additionally, characterizing probes by their genomic context can aid in interpreting the patterns of changes that are observed in a particular study set. This study added such information to the array probe set and was made publicly available to help others in interpretation of such complicated datasets.

The lab and collaborators had a fun baseball game that pitted a strong red team (Captain: Magda Price) against a formidable blue one (Captain John Blair). Despite home run hits by former little league star Sean Addison, and an excellent red team double play, blue took an early lead (aided by stellar pitching by BC Premier player Brendan Lim) that red was not able to overcome. Thanks especially to our colleagues from other labs for coming and joining in the fun!