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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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Global DNA methylation dynamics during the life cycle. Upon fertilization genome-wide DNA demethylation occurs in the zygote by conversion to 5hmC on the paternally derived genome and direct passive 5mC depletion of the maternally derived genome. The low-point of global methylation occurs at approximately E3.5 in the ICM, after which global re-methylation begins and reaches near completion by E6.5. At approximately E6.5, cells either continue to develop towards a somatic fate (left) or are specified as primordial germ cells (PGCs—right). Somatic fated cells acquire distinct methylomes according to their lineage but maintain high global levels of DNA methylation. PGCs initiate a phase of comprehensive DNA demethylation, which is complete by approximately  E12.5, and which enables subsequent establishment of a unique gamete-specific methylome during gametogenesis. Mature gametes can then fuse to form the zygote and initiate a new life cycle. ICM, inner cell mass.
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RSTB20110328F1: Global DNA methylation dynamics during the life cycle. Upon fertilization genome-wide DNA demethylation occurs in the zygote by conversion to 5hmC on the paternally derived genome and direct passive 5mC depletion of the maternally derived genome. The low-point of global methylation occurs at approximately E3.5 in the ICM, after which global re-methylation begins and reaches near completion by E6.5. At approximately E6.5, cells either continue to develop towards a somatic fate (left) or are specified as primordial germ cells (PGCs—right). Somatic fated cells acquire distinct methylomes according to their lineage but maintain high global levels of DNA methylation. PGCs initiate a phase of comprehensive DNA demethylation, which is complete by approximately  E12.5, and which enables subsequent establishment of a unique gamete-specific methylome during gametogenesis. Mature gametes can then fuse to form the zygote and initiate a new life cycle. ICM, inner cell mass.

Mentions: DNA methylation undergoes dynamic remodelling during early embryogenesis to initially establish a globally demethylated state and then subsequently, a progressively lineage-specific methylome that maintains cellular identity and genomic stability (figure 1). The process of extensive 5mC erasure begins in the zygote following fertilization and involves both conversion to 5hmC and direct passive depletion of 5mC [39]. Reprogramming of CpG methylation culminates in a globally demethylated genome in the inner cell mass (ICM) of the pre-implantation embryo (by approx. E3.5 in mice), and correlates with the establishment of pluripotent cells, which can form embryonic stem (ES) cells in vitro [17,40]. Indeed, ES cells completely lacking DNA methylation are viable and competent for self-renewal, indicating DNA methylation is dispensable for the naive ground state [41]. However, DNA methylation-deficient ES cells undergo apoptosis upon in vitro differentiation and Dnmt1- embryos die around approximately E8.5, suggesting that 5mC is a critical requirement to direct and maintain terminal cell differentiation in embryonic lineages [5]. Thus, the reduced genomic 5mC levels in the pre-implantation embryo generates an epigenetic state that is conducive for subsequent embryonic lineage-specification to proceed in parallel with de novo methylation to progressively lock in cellular identity.Figure 1.


DNA methylation dynamics during the mammalian life cycle.

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

Global DNA methylation dynamics during the life cycle. Upon fertilization genome-wide DNA demethylation occurs in the zygote by conversion to 5hmC on the paternally derived genome and direct passive 5mC depletion of the maternally derived genome. The low-point of global methylation occurs at approximately E3.5 in the ICM, after which global re-methylation begins and reaches near completion by E6.5. At approximately E6.5, cells either continue to develop towards a somatic fate (left) or are specified as primordial germ cells (PGCs—right). Somatic fated cells acquire distinct methylomes according to their lineage but maintain high global levels of DNA methylation. PGCs initiate a phase of comprehensive DNA demethylation, which is complete by approximately  E12.5, and which enables subsequent establishment of a unique gamete-specific methylome during gametogenesis. Mature gametes can then fuse to form the zygote and initiate a new life cycle. ICM, inner cell mass.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSTB20110328F1: Global DNA methylation dynamics during the life cycle. Upon fertilization genome-wide DNA demethylation occurs in the zygote by conversion to 5hmC on the paternally derived genome and direct passive 5mC depletion of the maternally derived genome. The low-point of global methylation occurs at approximately E3.5 in the ICM, after which global re-methylation begins and reaches near completion by E6.5. At approximately E6.5, cells either continue to develop towards a somatic fate (left) or are specified as primordial germ cells (PGCs—right). Somatic fated cells acquire distinct methylomes according to their lineage but maintain high global levels of DNA methylation. PGCs initiate a phase of comprehensive DNA demethylation, which is complete by approximately  E12.5, and which enables subsequent establishment of a unique gamete-specific methylome during gametogenesis. Mature gametes can then fuse to form the zygote and initiate a new life cycle. ICM, inner cell mass.
Mentions: DNA methylation undergoes dynamic remodelling during early embryogenesis to initially establish a globally demethylated state and then subsequently, a progressively lineage-specific methylome that maintains cellular identity and genomic stability (figure 1). The process of extensive 5mC erasure begins in the zygote following fertilization and involves both conversion to 5hmC and direct passive depletion of 5mC [39]. Reprogramming of CpG methylation culminates in a globally demethylated genome in the inner cell mass (ICM) of the pre-implantation embryo (by approx. E3.5 in mice), and correlates with the establishment of pluripotent cells, which can form embryonic stem (ES) cells in vitro [17,40]. Indeed, ES cells completely lacking DNA methylation are viable and competent for self-renewal, indicating DNA methylation is dispensable for the naive ground state [41]. However, DNA methylation-deficient ES cells undergo apoptosis upon in vitro differentiation and Dnmt1- embryos die around approximately E8.5, suggesting that 5mC is a critical requirement to direct and maintain terminal cell differentiation in embryonic lineages [5]. Thus, the reduced genomic 5mC levels in the pre-implantation embryo generates an epigenetic state that is conducive for subsequent embryonic lineage-specification to proceed in parallel with de novo methylation to progressively lock in cellular identity.Figure 1.

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