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

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      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.

      Author Summary

      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.

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      Most cited references 48

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      The University of California Santa Cruz (UCSC) Genome Browser ( offers online public access to a growing database of genomic sequence and annotations for a large collection of organisms, primarily vertebrates, with an emphasis on the human and mouse genomes. The Browser's web-based tools provide an integrated environment for visualizing, comparing, analysing and sharing both publicly available and user-generated genomic data sets. As of September 2013, the database contained genomic sequence and a basic set of annotation 'tracks' for ∼90 organisms. Significant new annotations include a 60-species multiple alignment conservation track on the mouse, updated UCSC Genes tracks for human and mouse, and several new sets of variation and ENCODE data. New software tools include a Variant Annotation Integrator that returns predicted functional effects of a set of variants uploaded as a custom track, an extension to UCSC Genes that displays haplotype alleles for protein-coding genes and an expansion of data hubs that includes the capability to display remotely hosted user-provided assembly sequence in addition to annotation data. To improve European access, we have added a Genome Browser mirror ( hosted at Bielefeld University in Germany.
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        Increased methylation variation in epigenetic domains across cancer types

        Summary Tumor heterogeneity is a major barrier to effective cancer diagnosis and treatment. We recently identified cancer-specific differentially DNA-methylated regions (cDMRs) in colon cancer, which also distinguish normal tissue types from each other, suggesting that these cDMRs might be generalized across cancer types. Here we show stochastic methylation variation of the same cDMRs, distinguishing cancer from normal, in colon, lung, breast, thyroid, and Wilms tumors, with intermediate variation in adenomas. Whole genome bisulfite sequencing shows these variable cDMRs are related to loss of sharply delimited methylation boundaries at CpG islands. Furthermore, we find hypomethylation of discrete blocks encompassing half the genome, with extreme gene expression variability. Genes associated with the cDMRs and large blocks are involved in mitosis and matrix remodeling, respectively. These data suggest a model for cancer involving loss of epigenetic stability of well-defined genomic domains that underlies increased methylation variability in cancer and could contribute to tumor heterogeneity.
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          The evolution of lncRNA repertoires and expression patterns in tetrapods.

          Only a very small fraction of long noncoding RNAs (lncRNAs) are well characterized. The evolutionary history of lncRNAs can provide insights into their functionality, but the absence of lncRNA annotations in non-model organisms has precluded comparative analyses. Here we present a large-scale evolutionary study of lncRNA repertoires and expression patterns, in 11 tetrapod species. We identify approximately 11,000 primate-specific lncRNAs and 2,500 highly conserved lncRNAs, including approximately 400 genes that are likely to have originated more than 300 million years ago. We find that lncRNAs, in particular ancient ones, are in general actively regulated and may function predominantly in embryonic development. Most lncRNAs evolve rapidly in terms of sequence and expression levels, but tissue specificities are often conserved. We compared expression patterns of homologous lncRNA and protein-coding families across tetrapods to reconstruct an evolutionarily conserved co-expression network. This network suggests potential functions for lncRNAs in fundamental processes such as spermatogenesis and synaptic transmission, but also in more specific mechanisms such as placenta development through microRNA production.

            Author and article information

            [1 ]Department of Medical Microbiology and Immunology, The University of California Davis School of Medicine, Davis, California, United States of America
            [2 ]University of California Davis Genome Center, University of California Davis, Davis, California, United States of America
            [3 ]University of California Davis MIND Institute, University of California Davis, Sacramento, California, United States of America
            [4 ]Department of Population Health and Reproduction, UC Davis School of Veterinary Medicine, Davis, California, United States of America
            [5 ]Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, United States of America
            [6 ]Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine, Davis, California, United States of America
            [7 ]Department of Surgical and Radiological Sciences, University of California School of Veterinary Medicine, Davis, California, United States of America
            [8 ]Department of Veterinary Sciences, University of Texas MD Anderson Cancer Center, Bastrop, Texas, United States of America
            [9 ]Department of Animal Science, University of California Davis, Davis, California, United States of America
            The Babraham Institute, UNITED KINGDOM
            Author notes

            The authors have declared that no competing interests exist.

            Conceived and designed the experiments: DIS JML. Performed the experiments: DIS KJ KCD TLT DY. Analyzed the data: DIS. Contributed reagents/materials/analysis tools: PJD LEW PBS PJR DLB GCD. Wrote the paper: DIS JML.

            Role: Editor
            PLoS Genet
            PLoS Genet
            PLoS Genetics
            Public Library of Science (San Francisco, CA USA )
            4 August 2015
            August 2015
            : 11
            : 8
            26241857 4524645 10.1371/journal.pgen.1005442 PGENETICS-D-15-00989

            This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

            Figures: 4, Tables: 0, Pages: 20
            This work was supported by Department of Defense AR110194, National Institutes of Health R01ES021707 and R01NS081913 (to JML), National Center for Research Resources R24 RR014214 (to PBS), and NIH ORIP grant number 8P40OD010938-Squirrel Monkey Breeding and Research Center Resource (to LEW). This work used the Vincent J. Coates Genomics Sequencing Laboratory at UC Berkeley, supported by National Center for Research Resources Instrumentation Grants S10RR029668 and S10RR027303. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Research Article
            Custom metadata
            MethylC-seq data are available from GEO under the accession number GSE63330.



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