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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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Mechanisms of DNA demethylation. Cytosine methylation (5mC) can be demethylated towards unmodified cytosine (C) through several potential mechanisms that can be broadly described as passive (left) or active (right). Passive demethylation occurs via replication-coupled dilution owing to a lack of re-establishment of DNA modification on the new daughter strand after DNA synthesis. Active erasure occurs through direct enzymatic removal of a DNA modification independent of DNA replication, and can involve a deamination reaction. Conversion to 5-hydroxymethylcytosine (5hmC) by TET proteins is likely a hub for demethylation (central box) and can lead to either passive or active erasure of DNA methylation. Additionally, 5hmC can be further modified to 5fC and 5caC (not shown), which can subsequently be actively or passively erased. 5mC can also be directly depleted passively, and potentially actively following deamination without conversion to 5hmC (upper arrows).
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RSTB20110328F2: Mechanisms of DNA demethylation. Cytosine methylation (5mC) can be demethylated towards unmodified cytosine (C) through several potential mechanisms that can be broadly described as passive (left) or active (right). Passive demethylation occurs via replication-coupled dilution owing to a lack of re-establishment of DNA modification on the new daughter strand after DNA synthesis. Active erasure occurs through direct enzymatic removal of a DNA modification independent of DNA replication, and can involve a deamination reaction. Conversion to 5-hydroxymethylcytosine (5hmC) by TET proteins is likely a hub for demethylation (central box) and can lead to either passive or active erasure of DNA methylation. Additionally, 5hmC can be further modified to 5fC and 5caC (not shown), which can subsequently be actively or passively erased. 5mC can also be directly depleted passively, and potentially actively following deamination without conversion to 5hmC (upper arrows).

Mentions: DNA methylation acts as a lineage-restricting barrier during development and it is therefore essential to reprogramme the stable 5mC mark to reset the life cycle for each new generation. The mechanisms that direct this process are of great interest and have recently begun to be unravelled (figure 2). In the zygote, DNA demethylation is mechanistically compartmentalized, with the maternally and paternally derived genomes undergoing distinct processes of 5mC erasure. Ultimately, this leads to a highly demethylated epigenome, with the exception of imprinted loci, rare maternally derived promoters and some transposable elements (TEs) including ETn and  intracisternal A particle (IAP) [30,59]. Original studies demonstrated that the paternal genome becomes globally demethylated prior to DNA replication, while the maternal genome apparently retains 5mC, with a subsequent progressive depletion over cell divisions [60,61]. This led to the suggestion that the paternal and maternal genomes undergo active and passive DNA demethylation, respectively. However, recent studies have demonstrated that at a global level paternal 5mC is converted to 5hmC, which is subsequently removed via passive replication-coupled dilution [39,62,63]. The paternal conversion to 5hmC is driven by the hydroxylase TET3, which can also further modify 5hmC to 5fC and 5caC [39,64]. Notably, maternal knockout of Tet3 leads to embryonic death in a subset of embryos suggesting the conversion to 5hmC is important, if not essential, to overcome the epigenetic barriers imposed by 5mC [65]. Thus, it appears that the bulk of zygotic demethylation is induced through passive replicative-dilution, but through different mechanisms on the paternal and maternal genomes. This difference may be related to the necessity to maintain genomic imprints through reprogramming, which are primarily located on the maternal genome [66]. Paternal imprints may be maintained via an alternative mechanism based on their association with repeat elements [67]. Interestingly, both the paternal and maternal genomes exhibit a dramatic decrease in 5mC, including at imprints, in mouse zygotes deficient for STELLA. This implies that the maternal genome is protected from 5hmC conversion, rather than the paternal genome being specifically targeted in normal zygotes [68]. However, it is unclear precisely how the direct passive loss of 5mC on the maternal genome occurs, as at least some DNMT1 is present and sufficient to maintain imprints [69].Figure 2.


DNA methylation dynamics during the mammalian life cycle.

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

Mechanisms of DNA demethylation. Cytosine methylation (5mC) can be demethylated towards unmodified cytosine (C) through several potential mechanisms that can be broadly described as passive (left) or active (right). Passive demethylation occurs via replication-coupled dilution owing to a lack of re-establishment of DNA modification on the new daughter strand after DNA synthesis. Active erasure occurs through direct enzymatic removal of a DNA modification independent of DNA replication, and can involve a deamination reaction. Conversion to 5-hydroxymethylcytosine (5hmC) by TET proteins is likely a hub for demethylation (central box) and can lead to either passive or active erasure of DNA methylation. Additionally, 5hmC can be further modified to 5fC and 5caC (not shown), which can subsequently be actively or passively erased. 5mC can also be directly depleted passively, and potentially actively following deamination without conversion to 5hmC (upper arrows).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSTB20110328F2: Mechanisms of DNA demethylation. Cytosine methylation (5mC) can be demethylated towards unmodified cytosine (C) through several potential mechanisms that can be broadly described as passive (left) or active (right). Passive demethylation occurs via replication-coupled dilution owing to a lack of re-establishment of DNA modification on the new daughter strand after DNA synthesis. Active erasure occurs through direct enzymatic removal of a DNA modification independent of DNA replication, and can involve a deamination reaction. Conversion to 5-hydroxymethylcytosine (5hmC) by TET proteins is likely a hub for demethylation (central box) and can lead to either passive or active erasure of DNA methylation. Additionally, 5hmC can be further modified to 5fC and 5caC (not shown), which can subsequently be actively or passively erased. 5mC can also be directly depleted passively, and potentially actively following deamination without conversion to 5hmC (upper arrows).
Mentions: DNA methylation acts as a lineage-restricting barrier during development and it is therefore essential to reprogramme the stable 5mC mark to reset the life cycle for each new generation. The mechanisms that direct this process are of great interest and have recently begun to be unravelled (figure 2). In the zygote, DNA demethylation is mechanistically compartmentalized, with the maternally and paternally derived genomes undergoing distinct processes of 5mC erasure. Ultimately, this leads to a highly demethylated epigenome, with the exception of imprinted loci, rare maternally derived promoters and some transposable elements (TEs) including ETn and  intracisternal A particle (IAP) [30,59]. Original studies demonstrated that the paternal genome becomes globally demethylated prior to DNA replication, while the maternal genome apparently retains 5mC, with a subsequent progressive depletion over cell divisions [60,61]. This led to the suggestion that the paternal and maternal genomes undergo active and passive DNA demethylation, respectively. However, recent studies have demonstrated that at a global level paternal 5mC is converted to 5hmC, which is subsequently removed via passive replication-coupled dilution [39,62,63]. The paternal conversion to 5hmC is driven by the hydroxylase TET3, which can also further modify 5hmC to 5fC and 5caC [39,64]. Notably, maternal knockout of Tet3 leads to embryonic death in a subset of embryos suggesting the conversion to 5hmC is important, if not essential, to overcome the epigenetic barriers imposed by 5mC [65]. Thus, it appears that the bulk of zygotic demethylation is induced through passive replicative-dilution, but through different mechanisms on the paternal and maternal genomes. This difference may be related to the necessity to maintain genomic imprints through reprogramming, which are primarily located on the maternal genome [66]. Paternal imprints may be maintained via an alternative mechanism based on their association with repeat elements [67]. Interestingly, both the paternal and maternal genomes exhibit a dramatic decrease in 5mC, including at imprints, in mouse zygotes deficient for STELLA. This implies that the maternal genome is protected from 5hmC conversion, rather than the paternal genome being specifically targeted in normal zygotes [68]. However, it is unclear precisely how the direct passive loss of 5mC on the maternal genome occurs, as at least some DNMT1 is present and sufficient to maintain imprints [69].Figure 2.

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