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

Schroeder DI, Jayashankar K, Douglas KC, Thirkill TL, York D, Dickinson PJ, Williams LE, Samollow PB, Ross PJ, Bannasch DL, Douglas GC, LaSalle JM - PLoS Genet. (2015)

Bottom Line: We found that, similar to human placenta, mammalian placentas and opossum extraembryonic membrane have globally lower levels of methylation compared to somatic tissues.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology and Immunology, The University of California Davis School of Medicine, Davis, California, United States of America; University of California Davis Genome Center, University of California Davis, Davis, California, United States of America; University of California Davis MIND Institute, University of California Davis, Sacramento, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Regions of high methylation are enriched for actively transcribed genes.(A) Relationship between average gene body percent methylation and gene expression in placentas. Only gene with orthologs were used. The right column shows a density scatterplot with gray and purple show areas of low and high density, respectively. Black lines show the marginal distribution of percent methylation in gene bodies. The left column shows the number of genes in each quadrant above/below what would be expected if gene expression and gene body methylation were independent. Human, mouse, and opossum expression data are from Necsulea et al. [30] (GSE43520) and horse expression data is from Wang et al. [31](GSE30243). (B) Comparison of methylation and gene expression patterns at the HECTD1 locus. Genes of interest are orange.
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pgen.1005442.g003: Regions of high methylation are enriched for actively transcribed genes.(A) Relationship between average gene body percent methylation and gene expression in placentas. Only gene with orthologs were used. The right column shows a density scatterplot with gray and purple show areas of low and high density, respectively. Black lines show the marginal distribution of percent methylation in gene bodies. The left column shows the number of genes in each quadrant above/below what would be expected if gene expression and gene body methylation were independent. Human, mouse, and opossum expression data are from Necsulea et al. [30] (GSE43520) and horse expression data is from Wang et al. [31](GSE30243). (B) Comparison of methylation and gene expression patterns at the HECTD1 locus. Genes of interest are orange.

Mentions: We next asked whether, as in human placenta, genes with high methylation are more likely to be expressed across a broad range of mammals with diverse placental anatomies [21]. Published polyA-selected RNA-seq data for human, mouse, and horse placenta and opossum EEM [30,31] were utilized to compare gene expression to gene body methylation in orthologous genes. In human placenta, expressed genes have clearly higher than average gene body methylation levels (Fig 3A, left column). To a lesser extent this can also be observed in mouse, horse, and opossum, although the range of gene body methylation values is smaller than human. To determine if these distributions are different than we would expect by chance given the marginal gene body methylation and gene expression distributions, we divided the x and y axes into 20 equally-spaced bins, counted the number of observations in each resulting quadrant, and compared that to the expected number of observations if gene body methylation and gene expression were independent (Fig 3A, right column). A co-independence test showed a statistically significant deviation from independence for all four species, but more importantly the patterns of deviation are remarkably similar between the species. In all species examined, genes with high gene body methylation are more likely to have intermediate expression than expected by chance and genes with low methylation are less likely to be expressed.


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

Schroeder DI, Jayashankar K, Douglas KC, Thirkill TL, York D, Dickinson PJ, Williams LE, Samollow PB, Ross PJ, Bannasch DL, Douglas GC, LaSalle JM - PLoS Genet. (2015)

Regions of high methylation are enriched for actively transcribed genes.(A) Relationship between average gene body percent methylation and gene expression in placentas. Only gene with orthologs were used. The right column shows a density scatterplot with gray and purple show areas of low and high density, respectively. Black lines show the marginal distribution of percent methylation in gene bodies. The left column shows the number of genes in each quadrant above/below what would be expected if gene expression and gene body methylation were independent. Human, mouse, and opossum expression data are from Necsulea et al. [30] (GSE43520) and horse expression data is from Wang et al. [31](GSE30243). (B) Comparison of methylation and gene expression patterns at the HECTD1 locus. Genes of interest are orange.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4524645&req=5

pgen.1005442.g003: Regions of high methylation are enriched for actively transcribed genes.(A) Relationship between average gene body percent methylation and gene expression in placentas. Only gene with orthologs were used. The right column shows a density scatterplot with gray and purple show areas of low and high density, respectively. Black lines show the marginal distribution of percent methylation in gene bodies. The left column shows the number of genes in each quadrant above/below what would be expected if gene expression and gene body methylation were independent. Human, mouse, and opossum expression data are from Necsulea et al. [30] (GSE43520) and horse expression data is from Wang et al. [31](GSE30243). (B) Comparison of methylation and gene expression patterns at the HECTD1 locus. Genes of interest are orange.
Mentions: We next asked whether, as in human placenta, genes with high methylation are more likely to be expressed across a broad range of mammals with diverse placental anatomies [21]. Published polyA-selected RNA-seq data for human, mouse, and horse placenta and opossum EEM [30,31] were utilized to compare gene expression to gene body methylation in orthologous genes. In human placenta, expressed genes have clearly higher than average gene body methylation levels (Fig 3A, left column). To a lesser extent this can also be observed in mouse, horse, and opossum, although the range of gene body methylation values is smaller than human. To determine if these distributions are different than we would expect by chance given the marginal gene body methylation and gene expression distributions, we divided the x and y axes into 20 equally-spaced bins, counted the number of observations in each resulting quadrant, and compared that to the expected number of observations if gene body methylation and gene expression were independent (Fig 3A, right column). A co-independence test showed a statistically significant deviation from independence for all four species, but more importantly the patterns of deviation are remarkably similar between the species. In all species examined, genes with high gene body methylation are more likely to have intermediate expression than expected by chance and genes with low methylation are less likely to be expressed.

Bottom Line: We found that, similar to human placenta, mammalian placentas and opossum extraembryonic membrane have globally lower levels of methylation compared to somatic tissues.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology and Immunology, The University of California Davis School of Medicine, Davis, California, United States of America; University of California Davis Genome Center, University of California Davis, Davis, California, United States of America; University of California Davis MIND Institute, University of California Davis, Sacramento, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus