Early Developmental and Evolutionary Origins of Gene Body DNA Methylation Patterns in Mammalian Placentas

Abstract

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.

Transposable Element Domestication As an Adaptation to Evolutionary Conflicts

“…A placenta feature that might facilitate the recurrent Syncytin cooption for placenta function could be the low level of DNA methylation relative to other tissues, which tends to promote the expression of TEs and endogenous retroviruses in particular in this organ [76, 79, 80]. In addition to the Syncytins , i.e., endogenous retrovirus gene domestication, numerous ERV and other TE sequences have been coopted as cis-regulatory elements to coordinate placental or uterine gene expression during pregnancy [81, 82].…”

Evolution of Epigenetic Regulation in Vertebrate Genomes

“…Mammalian placenta are remarkable for their conserved global hypomethylation compared to somatic tissues (less than 66% genome-wide methylation level by MethylC-seq in human, rhesus macaque, squirrel monkey, mouse, dog, horse, and cow placentas, as well as opossum extraembryonic membrane [56]). One exception to placental hypomethylation was that gene bodies displayed elevated methylation across all species.…”

“…One exception to placental hypomethylation was that gene bodies displayed elevated methylation across all species. As in somatic tissues, high methylation over gene bodies in the placenta correlated with intermediate gene expression level, while genes with low gene body methylation were less likely to be expressed [56]. Additionally, high placental gene body methylation was conserved across species over genes with similar gene ontologies, including genes involved in cell cycle, protein localization, and chromatin modification [56].…”

“…As in somatic tissues, high methylation over gene bodies in the placenta correlated with intermediate gene expression level, while genes with low gene body methylation were less likely to be expressed [56]. Additionally, high placental gene body methylation was conserved across species over genes with similar gene ontologies, including genes involved in cell cycle, protein localization, and chromatin modification [56]. Gene body methylation is a conserved feature of eukaryotic genomes, and methylation level has a parabolic relationship to gene expression level in most eukaryotic somatic tissues and placenta, although the mechanistic links between genic DNA methylation and expression level are still unclear.…”

Transcriptome Analysis of Non‐Coding RNAs in Livestock Species: Elucidating the Ambiguity

“…For example, De Vliegher et al [85] used miRbase [86] and UNAFold [87] for miRNA annotation and discovery in bovine mammary gland tissues while Peng et al [88] used miRbase [86] and RNAfold [89] for these purposes in porcine mammary glands. In our own studies, miRbase [86] and mirDeep2 [74] were used to identify miRNAs in various tissues including bovine mammary gland tissues [90], milk fat [90][91][92], milk whey and cells [90].…”