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DNA methylation, its mediators and genome integrity.

Meng H, Cao Y, Qin J, Song X, Zhang Q, Shi Y, Cao L - Int. J. Biol. Sci. (2015)

Bottom Line: DNA methylation regulates many cellular processes, including embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting and chromosome stability.DNA methyltransferases establish and maintain the presence of 5-methylcytosine (5mC), and ten-eleven translocation cytosine dioxygenases (TETs) oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be removed by base excision repair (BER) proteins.Thus, understanding functional genetic mutations and aberrant expression of these DNA methylation mediators is critical to deciphering the crosstalk between concurrent genetic and epigenetic alterations in specific cancer types and to the development of new therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: 1. Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China; ; 2. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, China.

ABSTRACT
DNA methylation regulates many cellular processes, including embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting and chromosome stability. DNA methyltransferases establish and maintain the presence of 5-methylcytosine (5mC), and ten-eleven translocation cytosine dioxygenases (TETs) oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be removed by base excision repair (BER) proteins. Multiple forms of DNA methylation are recognised by methyl-CpG binding proteins (MeCPs), which play vital roles in chromatin-based transcriptional regulation, DNA repair and replication. Accordingly, defects in DNA methylation and its mediators may cause silencing of tumour suppressor genes and misregulation of multiple cell cycles, DNA repair and chromosome stability genes, and hence contribute to genome instability in various human diseases, including cancer. Thus, understanding functional genetic mutations and aberrant expression of these DNA methylation mediators is critical to deciphering the crosstalk between concurrent genetic and epigenetic alterations in specific cancer types and to the development of new therapeutic strategies.

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Major forms and distribution of DNA methylation. (A) The three major forms of cytosine bases in mammalian DNA. The 5-position of cytosine is covalently methylated by DNA cytosine methyltransferases (DNMTs) with the presence of co-factor S-adenosyl methionine (SAM). The resulting 5-methylcytosine (5mC) is mostly found on CpG dinucleotides in somatic cells. 5-hydroxymethylcytosine (5hmC) is formed by methylation and subsequent hydroxylation and is mediated by the ten-eleven translocation cytosine dioxygenases (TETs). (B) Distribution of CpG dinucleotides in mammalian genomes. In vertebrate genomes, CpG dinucleotides are generally highly methylated, whereas CpG islands (CGIs) that are associated with gene promoters have exceptional global unmethylated patterns. Exceptions include CGIs on inactive X-chromosomes in female cells, where CGIs are hypermethylated. In addition to canonical CGIs located at annotated transcription start sites (TSSs), orphan CGIs of unknown function are found within gene bodies (intragenic) and between annotated genes (intergenic). Unmethylated CGIs at 5' ends of multiple genes are positively correlated with transcriptional activity (active, left), whereas a small number of genes are hypermethylated at their promoter CGIs and are repressed in specific cell types (inactive, right). Gene bodies are often methylated with higher DNA methylation at exons than introns, and 5hmC is present at expressed gene bodies and are the proposed 5mC oxidation products of TET enzymes (labelled white squares at body of gene). White circles, nonmethylated CpGs; black circles, methylated CpGs; white squares, hydroxylmethylated CpGs; red boxes, active and transcribed exons; black boxes, inactive and silenced exons; transcriptional states of these genes are represented by the red arrow (active) and the black cross (inactive).
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Figure 1: Major forms and distribution of DNA methylation. (A) The three major forms of cytosine bases in mammalian DNA. The 5-position of cytosine is covalently methylated by DNA cytosine methyltransferases (DNMTs) with the presence of co-factor S-adenosyl methionine (SAM). The resulting 5-methylcytosine (5mC) is mostly found on CpG dinucleotides in somatic cells. 5-hydroxymethylcytosine (5hmC) is formed by methylation and subsequent hydroxylation and is mediated by the ten-eleven translocation cytosine dioxygenases (TETs). (B) Distribution of CpG dinucleotides in mammalian genomes. In vertebrate genomes, CpG dinucleotides are generally highly methylated, whereas CpG islands (CGIs) that are associated with gene promoters have exceptional global unmethylated patterns. Exceptions include CGIs on inactive X-chromosomes in female cells, where CGIs are hypermethylated. In addition to canonical CGIs located at annotated transcription start sites (TSSs), orphan CGIs of unknown function are found within gene bodies (intragenic) and between annotated genes (intergenic). Unmethylated CGIs at 5' ends of multiple genes are positively correlated with transcriptional activity (active, left), whereas a small number of genes are hypermethylated at their promoter CGIs and are repressed in specific cell types (inactive, right). Gene bodies are often methylated with higher DNA methylation at exons than introns, and 5hmC is present at expressed gene bodies and are the proposed 5mC oxidation products of TET enzymes (labelled white squares at body of gene). White circles, nonmethylated CpGs; black circles, methylated CpGs; white squares, hydroxylmethylated CpGs; red boxes, active and transcribed exons; black boxes, inactive and silenced exons; transcriptional states of these genes are represented by the red arrow (active) and the black cross (inactive).

Mentions: Multiple forms of DNA methylation have been identified in mammals, including 5mC, the recently discovered 5-hydroxymethylcytosine (5hmC) and the ensuing oxidation products 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) 15-17. The major epigenetic modification 5mC and its hydroxylated derivative 5hmC are relatively stable and abundant in mammalian genomes 18 (Fig. 1A). In contrast, 5fC and 5caC are extremely rare and can be transiently removed by thymine DNA glycosylase (TDG) and are therefore speculated as active DNA demethylation intermediates 17, 19, 20. DNMTs produce 5mC by covalently adding a methyl group to the 5-position of the cytosine ring, predominantly occurring at CpG dinucleotides in somatic cells 21, 22. Mounting associations of 5mC with gene silencing indicate important roles in normal mammalian genomic imprinting, X-chromosome inactivation, repetitive element suppression and lineage-specific gene expression regulation 13, 23, 24. However, non-CpG methylation also occurs with high frequency in mouse and human embryonic stem (ES) cells and induced pluripotent stem cells 21, 22. The 5hmC intermediate was recently discovered as a second modification in vertebrate DNA and is formed by addition of a hydroxy group to 5mC by TETs 16, 25 (Fig. 1A). These enzymes are enriched in Purkinje neurons and ES cells 15, 16, and because 5hmC is more stable than its oxidation products 5fC and 5caC, the hydroxymethyl group is likely to have biological properties and may be an epigenetic mark 26, 27. Because 5mC and 5hmC are only distinguishable in experiments using 5hmC specific antibodies 28, 29, recent developments have been aimed at resolving 5hmC sites in the genome 30, 31. Nonetheless, it is accepted that 5mC is the most prominent modification in vertebrate DNA in the majority of mammalian tissues 32.


DNA methylation, its mediators and genome integrity.

Meng H, Cao Y, Qin J, Song X, Zhang Q, Shi Y, Cao L - Int. J. Biol. Sci. (2015)

Major forms and distribution of DNA methylation. (A) The three major forms of cytosine bases in mammalian DNA. The 5-position of cytosine is covalently methylated by DNA cytosine methyltransferases (DNMTs) with the presence of co-factor S-adenosyl methionine (SAM). The resulting 5-methylcytosine (5mC) is mostly found on CpG dinucleotides in somatic cells. 5-hydroxymethylcytosine (5hmC) is formed by methylation and subsequent hydroxylation and is mediated by the ten-eleven translocation cytosine dioxygenases (TETs). (B) Distribution of CpG dinucleotides in mammalian genomes. In vertebrate genomes, CpG dinucleotides are generally highly methylated, whereas CpG islands (CGIs) that are associated with gene promoters have exceptional global unmethylated patterns. Exceptions include CGIs on inactive X-chromosomes in female cells, where CGIs are hypermethylated. In addition to canonical CGIs located at annotated transcription start sites (TSSs), orphan CGIs of unknown function are found within gene bodies (intragenic) and between annotated genes (intergenic). Unmethylated CGIs at 5' ends of multiple genes are positively correlated with transcriptional activity (active, left), whereas a small number of genes are hypermethylated at their promoter CGIs and are repressed in specific cell types (inactive, right). Gene bodies are often methylated with higher DNA methylation at exons than introns, and 5hmC is present at expressed gene bodies and are the proposed 5mC oxidation products of TET enzymes (labelled white squares at body of gene). White circles, nonmethylated CpGs; black circles, methylated CpGs; white squares, hydroxylmethylated CpGs; red boxes, active and transcribed exons; black boxes, inactive and silenced exons; transcriptional states of these genes are represented by the red arrow (active) and the black cross (inactive).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4400391&req=5

Figure 1: Major forms and distribution of DNA methylation. (A) The three major forms of cytosine bases in mammalian DNA. The 5-position of cytosine is covalently methylated by DNA cytosine methyltransferases (DNMTs) with the presence of co-factor S-adenosyl methionine (SAM). The resulting 5-methylcytosine (5mC) is mostly found on CpG dinucleotides in somatic cells. 5-hydroxymethylcytosine (5hmC) is formed by methylation and subsequent hydroxylation and is mediated by the ten-eleven translocation cytosine dioxygenases (TETs). (B) Distribution of CpG dinucleotides in mammalian genomes. In vertebrate genomes, CpG dinucleotides are generally highly methylated, whereas CpG islands (CGIs) that are associated with gene promoters have exceptional global unmethylated patterns. Exceptions include CGIs on inactive X-chromosomes in female cells, where CGIs are hypermethylated. In addition to canonical CGIs located at annotated transcription start sites (TSSs), orphan CGIs of unknown function are found within gene bodies (intragenic) and between annotated genes (intergenic). Unmethylated CGIs at 5' ends of multiple genes are positively correlated with transcriptional activity (active, left), whereas a small number of genes are hypermethylated at their promoter CGIs and are repressed in specific cell types (inactive, right). Gene bodies are often methylated with higher DNA methylation at exons than introns, and 5hmC is present at expressed gene bodies and are the proposed 5mC oxidation products of TET enzymes (labelled white squares at body of gene). White circles, nonmethylated CpGs; black circles, methylated CpGs; white squares, hydroxylmethylated CpGs; red boxes, active and transcribed exons; black boxes, inactive and silenced exons; transcriptional states of these genes are represented by the red arrow (active) and the black cross (inactive).
Mentions: Multiple forms of DNA methylation have been identified in mammals, including 5mC, the recently discovered 5-hydroxymethylcytosine (5hmC) and the ensuing oxidation products 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) 15-17. The major epigenetic modification 5mC and its hydroxylated derivative 5hmC are relatively stable and abundant in mammalian genomes 18 (Fig. 1A). In contrast, 5fC and 5caC are extremely rare and can be transiently removed by thymine DNA glycosylase (TDG) and are therefore speculated as active DNA demethylation intermediates 17, 19, 20. DNMTs produce 5mC by covalently adding a methyl group to the 5-position of the cytosine ring, predominantly occurring at CpG dinucleotides in somatic cells 21, 22. Mounting associations of 5mC with gene silencing indicate important roles in normal mammalian genomic imprinting, X-chromosome inactivation, repetitive element suppression and lineage-specific gene expression regulation 13, 23, 24. However, non-CpG methylation also occurs with high frequency in mouse and human embryonic stem (ES) cells and induced pluripotent stem cells 21, 22. The 5hmC intermediate was recently discovered as a second modification in vertebrate DNA and is formed by addition of a hydroxy group to 5mC by TETs 16, 25 (Fig. 1A). These enzymes are enriched in Purkinje neurons and ES cells 15, 16, and because 5hmC is more stable than its oxidation products 5fC and 5caC, the hydroxymethyl group is likely to have biological properties and may be an epigenetic mark 26, 27. Because 5mC and 5hmC are only distinguishable in experiments using 5hmC specific antibodies 28, 29, recent developments have been aimed at resolving 5hmC sites in the genome 30, 31. Nonetheless, it is accepted that 5mC is the most prominent modification in vertebrate DNA in the majority of mammalian tissues 32.

Bottom Line: DNA methylation regulates many cellular processes, including embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting and chromosome stability.DNA methyltransferases establish and maintain the presence of 5-methylcytosine (5mC), and ten-eleven translocation cytosine dioxygenases (TETs) oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be removed by base excision repair (BER) proteins.Thus, understanding functional genetic mutations and aberrant expression of these DNA methylation mediators is critical to deciphering the crosstalk between concurrent genetic and epigenetic alterations in specific cancer types and to the development of new therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: 1. Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China; ; 2. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, China.

ABSTRACT
DNA methylation regulates many cellular processes, including embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting and chromosome stability. DNA methyltransferases establish and maintain the presence of 5-methylcytosine (5mC), and ten-eleven translocation cytosine dioxygenases (TETs) oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be removed by base excision repair (BER) proteins. Multiple forms of DNA methylation are recognised by methyl-CpG binding proteins (MeCPs), which play vital roles in chromatin-based transcriptional regulation, DNA repair and replication. Accordingly, defects in DNA methylation and its mediators may cause silencing of tumour suppressor genes and misregulation of multiple cell cycles, DNA repair and chromosome stability genes, and hence contribute to genome instability in various human diseases, including cancer. Thus, understanding functional genetic mutations and aberrant expression of these DNA methylation mediators is critical to deciphering the crosstalk between concurrent genetic and epigenetic alterations in specific cancer types and to the development of new therapeutic strategies.

Show MeSH
Related in: MedlinePlus