Project description:The Mammalian Methylation Consortium aimed to characterize the relationship between cytosine methylation levels and a) species characteristics such as maximum lifespan and b) individual sample characteristics such as age, sex, tissue type. Both supervised machine learning approaches and unsupervised machine learning approaches were applied to the data as described in the citations. To facilitate comparative analyses across species, the mammalian methylation consortium applied a single measurement platform (the mammalian methylation array, GPL28271) to n=15216 DNA samples derived from 70 tissue types of 348 different mammalian species (331 eutherian-, 15 marsupial-, and 2 monotreme species). Most of the CpGs are located in highly conserved stretches of DNA but not all CpGs apply to all species as detailed in the description of the platform, GPL28271 and on https://github.com/shorvath/MammalianMethylationConsortium/.
Project description: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 methylation 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. However, not all species have clear PMD/HMDs in their placentas. Instead what is conserved is higher methylation over the bodies of genes involved in mitosis, vesicle-mediated transport, protein phosphorylation, and chromatin modification compared with the rest of the genome. As in human placenta, high gene body methylation is associated with higher gene expression across species. Analysis of DNA methylation in mouse and cow oocytes shows the same pattern of gene body methylation over many of the same genes as in the placenta, suggesting that this conserved pattern of active gene body methylation of the placenta may be established very early in development. MethylC-seq on placentas of 7 mammals, trophoblasts of rhesus, brains of 3 mammals, oocytes of cow, and human cordblood
Project description:This SuperSeries is composed of the SubSeries listed below. Consortium contacts: Maria Pedersen: mpedersen@nygenome.org Hemali Phatnani: hphatnani@nygenome.org NYGC ALS Consortium: cgndhelp@nygenome.org
Project description:Our study supports a role for H3K9 methylation in promoting DNA methylation, it demonstrates for the first time that DNA maintenance methylation in mammalian cells is to large extent independent on H3K9 methylation. Examination of DNA methylation levels in UHRF1 knock in and wide type mice.
Project description:H3K4 methylation is associated with active genes and, along with H3K27 methylation, is part of a bivalent chromatin mark that typifies poised developmental genes in ESCs. However, its functional roles in ESC maintenance and differentiation are not established. Here we show that mammalian Dpy-30, a core subunit of SET1/MLL complexes, biochemically modulates H3K4 methylation in vitro, and directly regulates chromosomal H3K4me3 throughout the mammalian genome. Depletion of Dpy-30 does not affect ESC self-renewal, but significantly alters the differentiation potential of ESCs, particularly along the neural lineage. The differentiation defect is accompanied by defects in gene induction and H3K4 methylation at key developmental loci. Our results provide strong experimental evidence for the hypothesis that H3K4 methylation is an essential functional component of the bivalent mark during activation of developmental genes in ESCs. Total RNAs from control or knockdown cells before and after RA-mediated differentiation were subjected to Illumina microarray analyses. ChIP-enriched DNA from mouse ES cells was analyzed by Solexa sequencing.
Project description: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 methylation 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. However, not all species have clear PMD/HMDs in their placentas. Instead what is conserved is higher methylation over the bodies of genes involved in mitosis, vesicle-mediated transport, protein phosphorylation, and chromatin modification compared with the rest of the genome. As in human placenta, high gene body methylation is associated with higher gene expression across species. Analysis of DNA methylation in mouse and cow oocytes shows the same pattern of gene body methylation over many of the same genes as in the placenta, suggesting that this conserved pattern of active gene body methylation of the placenta may be established very early in development.
Project description:Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing. Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter. Targeted demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1 induced BDNF expression in post-mitotic neurons or activated MyoD facilitating reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and interfered with DNA looping, causing altered gene expression in the neighboring loop. Finally, we show that these tools can edit DNA methylation in mice demonstrating their wide utility for functional studies of epigenetic regulation.