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WIREs Syst Biol Med
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Mediators and dynamics of DNA methylation

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Abstract As an inherited epigenetic marker occurring mainly on cytosines at CpG dinucleotides, DNA methylation occurs across many higher eukaryotic organisms. Looking at methylation patterns genome‐wide classifies cell types uniquely and in several cases discriminates between healthy and cancerous cell types. DNA methylation can occur allele‐specifically, which allows the cellular regulatory machinery to recognize each allele separately. Although only a small number of allele specifically methylated (ASM) regions are known, genome‐wide experiments show that ASM is prevalent throughout the human genome. These DNA methylation patterns can be modified via DNA demethylation, which is important for induced pluripotent stem reprogramming and primordial germ cells. Recent evidence shows that the protein activation‐induced cytidine deaminase plays a critical role in these demethylation events. Many transcription factors mediate DNA methylation patterns. Some transcription factors bind specifically to methylated or unmethylated sequences and other transcription factors protect genomic regions (e.g., promoter regions) from nearby DNA methylation encroachment. Possibly acting as another epigenetic regulatory layer, methylated cytosines are also converted to 5‐hydroxyethylcyotines, which is a new modification type whose biological significance has yet been defined. WIREs Syst Biol Med 2011 3 281–298 DOI: 10.1002/wsbm.124 This article is categorized under: Laboratory Methods and Technologies > Genetic/Genomic Methods Biological Mechanisms > Regulatory Biology

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Methylation frequency differences between differentiated and pluripotent cell lines. (a) This figure shows the methylation status of H1 (ES cell) and IMR90 (fibroblast cell) across a 3 kb region of chromosome 6. Each vertical bar represents a CpG site whose color is dependent on its methylation level. The arrow indicates the promoter of Pou5F1, which codes for the Oct4 protein. Oct4 is a master regulatory of pluripotency in ES cells. The promoter is unmethylated in H1, where Oct4 is transcribed, and methylated in IMR90, where Oct4 is repressed. Regions upstream of the Pou5F1 promoter show larges swaths of differential methylation. Successfully reprogramming involving large methylation changes in such areas. (b) A detailed view of the DNMT3b TSS site across 13 cell lines. The arrows indicate CpG sites that show cell type specific methylation. The iPS lines have methylation signatures that match the ES cells instead of their pretransformed cell types. PGP_1 is a lymphoblastoid cell line while PGP1_F, IMR90, BJ, and hFib2 are fibroblast cell lines. PGP1_iPS1 was transformed from the PGP1 fibroblast. Hues12, Hues42, and Hues63 are embryonic stem cell lines.

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ASM examples. (a) A schematic of typical ASM. The two alleles are represented separately as blue and orange lines. A SNP distinguishes the alleles and the blue allele is methylated while the orange allele is not. This is considered an ASM region. (b) This figure shows a gene whose promoter region is methylated in the blue allele and unmethylated in the orange allele. A SNP site at the promoter distinguishes the alleles. Additionally, another SNP site in an exon differentiates the alleles. This figure shows how ASM can be used to predict ASE behavior. Additional haplotyping can associate the SNPs thereby allele specifically linking the methylation status of a regulatory region to its expression. (c) An instance of a SNP overlapping with a CpG site in an ASM region. The SNP in this example disrupts a CpG site such that the CpG site no longer exists in the orange allele. The ASM behavior seen in this region may be caused by the SNP itself or the SNP/CpG overlap. (d) An instance of a SNP overlapping with a CpG site in a non‐ASM region. Similar to (c), the overlapped CpG site no longer exists in the orange allele.

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Cell type specificity of DNA methylation. This figure shows the dissimilarity of cell types based on their methylation frequencies from targeted bisulfite data that covered CpG islands on chr12 and chr20. Cell types that are closer together share a more similar methylation signature. The fibroblasts, PGP1F (Personal Genome Foundation 1 Fibroblast), BJ, IMR90, and hFib2 (human Fibroblast), cluster closely together, while the lymphoblasts PGP9L (Personal Genome Project 9 Lymphoblast), PGP3L, and PGP1L also cluster together closely. Regarding the pluripotent cell lines, the ES cells (Hues12, Hues42, and Hues63) cluster very closely together. The hybrid cell line, which consists of fused nuclei from Hues6 and BJ, also clusters closely with the ES cell group. The induced pluripotent stem (iPS) lines appear to be much more similar to the ES cell group than the differentiated fibroblasts and lymphoblasts but the iPS group exhibits a wider spectrum of methylation signatures than the ES cell group or the two differentiate cell groups.

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Structures of in vivo cytosine modifications found in humans. This figure shows the structure of cytosine and its two modified forms found in the human genome.

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Biological Mechanisms > Regulatory Biology
Laboratory Methods and Technologies > Genetic/Genomic Methods

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