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DNA methylation dynamics during the mammalian life cycle.

Hackett JA, Surani MA - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2013)

Bottom Line: DNA methylation contributes to the epigenetic regulation of many key developmental processes including genomic imprinting, X-inactivation, genome stability and gene regulation.Additionally, there is a better understanding of the mechanistic basis of DNA demethylation during epigenetic reprogramming in primordial germ cells and during pre-implantation development.Here, we discuss our current understanding of the developmental roles and dynamics of this key epigenetic system.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.

ABSTRACT
DNA methylation is dynamically remodelled during the mammalian life cycle through distinct phases of reprogramming and de novo methylation. These events enable the acquisition of cellular potential followed by the maintenance of lineage-restricted cell identity, respectively, a process that defines the life cycle through successive generations. DNA methylation contributes to the epigenetic regulation of many key developmental processes including genomic imprinting, X-inactivation, genome stability and gene regulation. Emerging sequencing technologies have led to recent insights into the dynamic distribution of DNA methylation during development and the role of this epigenetic mark within distinct genomic contexts, such as at promoters, exons or imprinted control regions. Additionally, there is a better understanding of the mechanistic basis of DNA demethylation during epigenetic reprogramming in primordial germ cells and during pre-implantation development. Here, we discuss our current understanding of the developmental roles and dynamics of this key epigenetic system.

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Distribution and roles of DNA methylation. The distribution of DNA methylation varies according to genomic landmarks. High-CpG density promoters (HCP) are usually hypomethylated, low CpG-density promoters (LCP) are usually methylated, and intermediate CpG-density promoters (ICP) can be either methylated or unmethylated (shown as shaded). In general, methylation only has a significant transcriptional effect at HCPs and ICPs, whereas methylation at LCPs does not correlate with repression. Note also that the absence of methylation only generates a permissive state for transcription and does not necessarily result in gene activity. Imprinted loci are methylated on one allele and hypomethylated on the other. This can have allele-specific effects by either modulating interactions between enhancers (green) and promoters (upper imprinted gene) or regulating expression of an antisense ncRNA, which silences genes in cis (lower imprinted gene). Gene bodies are generally hypermethylated, which may function to repress cryptic internal promoters. Transposable elements are usually highly methylated in the promoter and coding regions, which silences their expression and can lead to their mutation and inactivation through cytosine deamination (asterisks), respectively. A1/A2: Allele 1 and Allele 2. DMR, differentially methylated region.
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RSTB20110328F3: Distribution and roles of DNA methylation. The distribution of DNA methylation varies according to genomic landmarks. High-CpG density promoters (HCP) are usually hypomethylated, low CpG-density promoters (LCP) are usually methylated, and intermediate CpG-density promoters (ICP) can be either methylated or unmethylated (shown as shaded). In general, methylation only has a significant transcriptional effect at HCPs and ICPs, whereas methylation at LCPs does not correlate with repression. Note also that the absence of methylation only generates a permissive state for transcription and does not necessarily result in gene activity. Imprinted loci are methylated on one allele and hypomethylated on the other. This can have allele-specific effects by either modulating interactions between enhancers (green) and promoters (upper imprinted gene) or regulating expression of an antisense ncRNA, which silences genes in cis (lower imprinted gene). Gene bodies are generally hypermethylated, which may function to repress cryptic internal promoters. Transposable elements are usually highly methylated in the promoter and coding regions, which silences their expression and can lead to their mutation and inactivation through cytosine deamination (asterisks), respectively. A1/A2: Allele 1 and Allele 2. DMR, differentially methylated region.

Mentions: At the cellular level DNA methylation is essential to propagate lineage restriction and to maintain genomic stability. However, at the molecular level the role of 5mC is dictated by multiple parameters, including its genomic context—such as promoter or exon, the local CpG density and local chromatin modifications [10,83]. While DNA methylation is generally considered to impede and repress transcription, genome-wide studies have demonstrated that the actual transcriptional effect of DNA methylation at promoter regions is related to the local CpG-density (figure 3) [9,84]. For example, DNA methylation at low CpG-density promoters (LCP) is not correlated with transcriptional silencing, and indeed most LCPs are methylated irrespective of their expression state. In contrast, significant 5mC at high CpG-density promoters (HCP) is strongly associated with gene silencing, although HCPs are very rarely methylated during normal development, excepting imprinted genes and the inactive X-chromosome. Thus, concerning transcriptional regulation, DNA methylation primarily functions at intermediate CpG-density promoters (ICP), which have a greater capacity to acquire lineage-dependent methylation and which are also correlated with strong gene silencing when methylated [9,30]. Of particular prominence is a role for DNA methylation in stably silencing ICPs associated with germline-specific genes [9,85,86], which may serve to stringently prevent their expression in somatic cells owing to their potential for contributing to carcinogenesis [87,88]. Further studies have shown that promoter methylation at germline-specific genes is indeed uniquely associated with their transcriptional regulation [89]. At other promoters, principally lineage- or pluripotency-specific genes, CpG methylation may function as a secondary ‘silencing lock’ that is acquired after other chromatin modifications have established a repressive state [90]. However, CpG methylation is generally not a regulatory mechanism that causally directs repression at most promoters during normal development. Indeed, it has even been reported to mediate gene activation in some rare contexts [91].Figure 3.


DNA methylation dynamics during the mammalian life cycle.

Hackett JA, Surani MA - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2013)

Distribution and roles of DNA methylation. The distribution of DNA methylation varies according to genomic landmarks. High-CpG density promoters (HCP) are usually hypomethylated, low CpG-density promoters (LCP) are usually methylated, and intermediate CpG-density promoters (ICP) can be either methylated or unmethylated (shown as shaded). In general, methylation only has a significant transcriptional effect at HCPs and ICPs, whereas methylation at LCPs does not correlate with repression. Note also that the absence of methylation only generates a permissive state for transcription and does not necessarily result in gene activity. Imprinted loci are methylated on one allele and hypomethylated on the other. This can have allele-specific effects by either modulating interactions between enhancers (green) and promoters (upper imprinted gene) or regulating expression of an antisense ncRNA, which silences genes in cis (lower imprinted gene). Gene bodies are generally hypermethylated, which may function to repress cryptic internal promoters. Transposable elements are usually highly methylated in the promoter and coding regions, which silences their expression and can lead to their mutation and inactivation through cytosine deamination (asterisks), respectively. A1/A2: Allele 1 and Allele 2. DMR, differentially methylated region.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539357&req=5

RSTB20110328F3: Distribution and roles of DNA methylation. The distribution of DNA methylation varies according to genomic landmarks. High-CpG density promoters (HCP) are usually hypomethylated, low CpG-density promoters (LCP) are usually methylated, and intermediate CpG-density promoters (ICP) can be either methylated or unmethylated (shown as shaded). In general, methylation only has a significant transcriptional effect at HCPs and ICPs, whereas methylation at LCPs does not correlate with repression. Note also that the absence of methylation only generates a permissive state for transcription and does not necessarily result in gene activity. Imprinted loci are methylated on one allele and hypomethylated on the other. This can have allele-specific effects by either modulating interactions between enhancers (green) and promoters (upper imprinted gene) or regulating expression of an antisense ncRNA, which silences genes in cis (lower imprinted gene). Gene bodies are generally hypermethylated, which may function to repress cryptic internal promoters. Transposable elements are usually highly methylated in the promoter and coding regions, which silences their expression and can lead to their mutation and inactivation through cytosine deamination (asterisks), respectively. A1/A2: Allele 1 and Allele 2. DMR, differentially methylated region.
Mentions: At the cellular level DNA methylation is essential to propagate lineage restriction and to maintain genomic stability. However, at the molecular level the role of 5mC is dictated by multiple parameters, including its genomic context—such as promoter or exon, the local CpG density and local chromatin modifications [10,83]. While DNA methylation is generally considered to impede and repress transcription, genome-wide studies have demonstrated that the actual transcriptional effect of DNA methylation at promoter regions is related to the local CpG-density (figure 3) [9,84]. For example, DNA methylation at low CpG-density promoters (LCP) is not correlated with transcriptional silencing, and indeed most LCPs are methylated irrespective of their expression state. In contrast, significant 5mC at high CpG-density promoters (HCP) is strongly associated with gene silencing, although HCPs are very rarely methylated during normal development, excepting imprinted genes and the inactive X-chromosome. Thus, concerning transcriptional regulation, DNA methylation primarily functions at intermediate CpG-density promoters (ICP), which have a greater capacity to acquire lineage-dependent methylation and which are also correlated with strong gene silencing when methylated [9,30]. Of particular prominence is a role for DNA methylation in stably silencing ICPs associated with germline-specific genes [9,85,86], which may serve to stringently prevent their expression in somatic cells owing to their potential for contributing to carcinogenesis [87,88]. Further studies have shown that promoter methylation at germline-specific genes is indeed uniquely associated with their transcriptional regulation [89]. At other promoters, principally lineage- or pluripotency-specific genes, CpG methylation may function as a secondary ‘silencing lock’ that is acquired after other chromatin modifications have established a repressive state [90]. However, CpG methylation is generally not a regulatory mechanism that causally directs repression at most promoters during normal development. Indeed, it has even been reported to mediate gene activation in some rare contexts [91].Figure 3.

Bottom Line: DNA methylation contributes to the epigenetic regulation of many key developmental processes including genomic imprinting, X-inactivation, genome stability and gene regulation.Additionally, there is a better understanding of the mechanistic basis of DNA demethylation during epigenetic reprogramming in primordial germ cells and during pre-implantation development.Here, we discuss our current understanding of the developmental roles and dynamics of this key epigenetic system.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.

ABSTRACT
DNA methylation is dynamically remodelled during the mammalian life cycle through distinct phases of reprogramming and de novo methylation. These events enable the acquisition of cellular potential followed by the maintenance of lineage-restricted cell identity, respectively, a process that defines the life cycle through successive generations. DNA methylation contributes to the epigenetic regulation of many key developmental processes including genomic imprinting, X-inactivation, genome stability and gene regulation. Emerging sequencing technologies have led to recent insights into the dynamic distribution of DNA methylation during development and the role of this epigenetic mark within distinct genomic contexts, such as at promoters, exons or imprinted control regions. Additionally, there is a better understanding of the mechanistic basis of DNA demethylation during epigenetic reprogramming in primordial germ cells and during pre-implantation development. Here, we discuss our current understanding of the developmental roles and dynamics of this key epigenetic system.

Show MeSH
Related in: MedlinePlus