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Evidence That Three Classes of Methylomes Specific for Stem, Somatic and Transformed Cells Are Set by Three Independent Mechanisms (Methyl-Seq)

ABSTRACT: Whole genome-bisulfite sequencing has revealed that methylomes differ dramatically in a cell type-specific manner. However, the global mechanisms of maintenance of DNA methylation patterns and their functional consequences are not clear. Using a combination of novel haplotype-resolved methylomes and publicly available data, we show that three distinct classes of methylomes that differ by the proportion of partially and highly methylated domains are characteristic of stem and progenitor, somatic and transformed cells. We provide evidence that three mechanisms can account for most of the differences between these three classes of methylomes. The first, protection of promoters and cis-acting regulatory elements from DNA methylation by DNA-binding proteins, keeps regulatory elements unmethylated. The second, DNA replication-associated maintenance of DNA methylation, is highly efficient in stem cells, moderately efficient in somatic cells, and very inefficient in transformed cells, and sets variable basal levels of methylation characteristic of the partially methylated domains of each cell type. The third, transcriptional elongation-associated gene-body DNA methylation is responsible for the formation of highly methylated domains in somatic and transformed cells. We show that partitioning of the genome into partially and highly methylated domains is associated with different mechanisms of gene silencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84998 | GEO | 2019/07/23

REPOSITORIES: GEO

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Project description:Embryogenesis is tightly regulated by multiple levels of epigenetic systems such as DNA methylation, histone modification, and chromatin remodeling. DNA methylation patterns are erased in primordial germ cells and in the interval immediately following fertilization. Subsequent reprogramming occurs by de novo methylation and demethylation. Variance of DNA methylation patterns between different cell types is not well understood. Here, using methylated DNA immunoprecipitation and tiling array technology, we have comprehensively analysed DNA methylation patterns at proximal promoter regions in mouse embryonic stem (ES) cells, ES cell-derived early germ layers (ectoderm, endoderm and mesoderm) and four adult tissues (brain, liver, skeletal muscle and sperm). Most of the methylated regions in the three germ layers and in the three adult somatic tissues are shared in common. This commonly methylated gene set is enriched in germ cell associated genes that are generally transcriptionally inactive in somatic cells. We also compared DNA methylation patterns with global mapping of histone H3 lysine 4/27 trimethylation, and found that gain of DNA methylation correlates with loss of histone H3 lysine 4 trimethylation. Taken together, our findings indicate that differentiation from ES cells to the three germ layers is accompanied by an increase in the number of commonly methylated DNA regions and that these tissue-specific alterations are present for only a small number of genes. Our findings indicate that DNA methylation at the proximal promoter regions of commonly methylated genes act as an irreversible mark which fixes somatic lineage by repressing transcription of germ cell specific genes. Using the MeDIP on chip protocol, we immunoprecipitated methylated DNA from R1 ES cell, SK7 cell, as well as SK7 derived-Ectoderm, - Endoderm, -Paraxial mesoderm, brain, liver, skeletal muscle, and sperm, and hybridized to a genome tiling array. The three germ layer lineages from ES cells were confirmed by the expression of specific marker genes in each germ layer (see related expression analysis).

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Evidence That Three Classes of Methylomes Specific for Stem, Somatic and Transformed Cells Are Set by Three Independent Mechanisms (Methyl-Seq)

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