The human placental methylome was the first normal tissue where partially methylated domains (PMDs) were characterized, found to be developmentally dynamic, and distinct from highly methylated domains (HMDs, methylation >70%).
PMDs are a large scale genomic feature with DNA methylation levels that are less than 70% but nowhere near 0% and tend to harbour neuron specific genes. In human placenta, PMDs and HMDs are distinct large scale domains that show a bimodal distribution and can cover entire gene clusters. However, the evolutionary origins of such a large scale epigenomic feature in humans has remained a mystery.
Diane Schroeder of the LaSalle lab at UC Davis led an interesting study recently shedding some light on DNA methylation in the placenta. According to Schroeder, “In human placenta, genes within PMDs are repressed. It’s still unknown whether partial methylation plays a part in the gene repression or whether partial methylation is, for example, a side effect of chromatin inaccessibility. However, for this study we had hoped to use PMDs to trace the evolution of gene regulation in mammalian placentas.”
In order to crack this evolutionary mystery the team used MethylC-seq to analyze the placentas of a number of mammals (human, rhesus macaque, squirrel monkey, mouse, dog, horse, and cow) as well as a marsupial (opossum) extraembryonic membrane (EEM).
Here’s what they found:
- Mammalian placentas and EEM show lower global methylation than somatic tissues, just like in humans.
- Evolution threw a curveball and there was no discrete bimodal distribution of PMDs and HMDs in the placentas of many species.
- Global methylation showed no correlation to evolutionary relationship.
- Adjusting to the funky pitches of evolution, the team found that high methylation over gene bodies, particularly expressed ones, was a conserved feature across all species that can be used to predict the location of genes.
- This methylation was typically over single genes and not gene clusters, just like in non-human placentas with PMDs/HMDs.
- Shedding light on the evolutionary origin of placentas in mammals, it was found that the EEM also has low global methylation and high methylation levels in gene bodies.
- Intriguingly, oocytes and preimplantation embryos shared this pattern.
Schroeder shares her surprise that, “the PMD story turned out to be much more complicated because although all placentas had hypomethylation, not all had a clear delineation between PMDs and HMDs like the human placenta had. Intriguingly, though, all species had higher methylation over the gene bodies of a specific subset of genes. Those genes also had higher expression in the placentas. But what was really exciting was seeing those same genes have both higher gene body methylation and higher expression in oocytes and early embryos as well. This suggests that placenta retains a small signature of the regulatory program that was set up very early in development.”
LaSalle concludes, “Understanding the methylation rules in early life is important for future studies in identifying epigenetic biomarkers in placenta (an accessible tissue usually discarded at birth) and in cancer, where the methylome is more similar to placenta than normal somatic tissues.”
Get the full digest of placenta over at PLOS Genetics, August 2015