Diane I. Schroeder 1 , 2 , 3 , Kartika Jayashankar 4 , Kory C. Douglas 5 , Twanda L. Thirkill 6 , Daniel York 7 , Pete J. Dickinson 7 , Lawrence E. Williams 8 , Paul B. Samollow 5 , Pablo J. Ross 9 , Danika L. Bannasch 4 , Gordon C. Douglas 6 , Janine M. LaSalle 1 , 2 , 3 , *
4 August 2015
Over the last 20-80 million years the mammalian placenta has taken on a variety of morphologies through both divergent and convergent evolution. Recently we have shown that the human placenta genome has a unique epigenetic pattern of large partially methylated domains (PMDs) and highly methylated domains (HMDs) with gene body DNA methylation positively correlating with level of gene expression. In order to determine the evolutionary conservation of DNA methylation patterns and transcriptional regulatory programs in the placenta, we performed a genome-wide methylome (MethylC-seq) analysis of human, rhesus macaque, squirrel monkey, mouse, dog, horse, and cow placentas as well as opossum extraembryonic membrane. We found that, similar to human placenta, mammalian placentas and opossum extraembryonic membrane have globally lower levels of methylation compared to somatic tissues. Higher relative gene body methylation was the conserved feature across all mammalian placentas, despite differences in PMD/HMDs and absolute methylation levels. Specifically, higher methylation over the bodies of genes involved in mitosis, vesicle-mediated transport, protein phosphorylation, and chromatin modification was observed compared with the rest of the genome. As in human placenta, higher methylation is associated with higher gene expression and is predictive of genic location across species. Analysis of DNA methylation in oocytes and preimplantation embryos shows a conserved pattern of gene body methylation similar to the placenta. Intriguingly, mouse and cow oocytes and mouse early embryos have PMD/HMDs but their placentas do not, suggesting that PMD/HMDs are a feature of early preimplantation methylation patterns that become lost during placental development in some species and following implantation of the embryo.
The placenta is vital for the proper development of the fetus, not only facilitating the exchange of nutrients, oxygen, and waste between the mother and the fetus but also acting as an interface to the maternal immune system and regulating fetal growth by excreting hormones and growth factors. DNA methylation is important for both placental and embryonic development as loss of proteins involved in DNA methylation can result in placental dysmorphology and early embryonic death. The human placenta has a unique DNA methylation landscape characterized by alternating regions of low methylation, covering silent genes with tissue-specific developmental functions, and high methylation, covering active genes. In order to better understand the significance of this DNA methylation landscape in the human placenta, we performed a cross-species comparison of DNA methylation in mammalian placentas, oocytes, and early embryos from this and other studies. Although the levels and extent of hypomethylation differed between mammalian placentas, what we found to be highly conserved was relatively higher methylation levels over active genes. These same genes also had high methylation in the opossum extraembryonic membrane, a primitive placenta, as well as oocytes and early embryos, suggesting that high methylation over these genes predated placental mammals and is established very early in development.