Busy Winter

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.

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