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Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers.

Seisenberger S, Peat JR, Hore TA, Santos F, Dean W, Reik W - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2013)

Bottom Line: Deamination by AID, BER and passive demethylation have been implicated in reprogramming in PGCs, but the process in its entirety is still poorly understood.In this review, we discuss the dynamics of DNA methylation reprogramming in PGCs and the zygote, the mechanisms involved and the biological significance of these events.Conversely, insights into in vitro reprogramming techniques may aid our understanding of epigenetic reprogramming in the germline and supply important clues in reprogramming for therapies in regenerative medicine.

View Article: PubMed Central - PubMed

Affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK. stefanie.seisenberger@babraham.ac.uk

ABSTRACT
In mammalian development, epigenetic modifications, including DNA methylation patterns, play a crucial role in defining cell fate but also represent epigenetic barriers that restrict developmental potential. At two points in the life cycle, DNA methylation marks are reprogrammed on a global scale, concomitant with restoration of developmental potency. DNA methylation patterns are subsequently re-established with the commitment towards a distinct cell fate. This reprogramming of DNA methylation takes place firstly on fertilization in the zygote, and secondly in primordial germ cells (PGCs), which are the direct progenitors of sperm or oocyte. In each reprogramming window, a unique set of mechanisms regulates DNA methylation erasure and re-establishment. Recent advances have uncovered roles for the TET3 hydroxylase and passive demethylation, together with base excision repair (BER) and the elongator complex, in methylation erasure from the zygote. Deamination by AID, BER and passive demethylation have been implicated in reprogramming in PGCs, but the process in its entirety is still poorly understood. In this review, we discuss the dynamics of DNA methylation reprogramming in PGCs and the zygote, the mechanisms involved and the biological significance of these events. Advances in our understanding of such natural epigenetic reprogramming are beginning to aid enhancement of experimental reprogramming in which the role of potential mechanisms can be investigated in vitro. Conversely, insights into in vitro reprogramming techniques may aid our understanding of epigenetic reprogramming in the germline and supply important clues in reprogramming for therapies in regenerative medicine.

Show MeSH
DNA methylation reprogramming in the mammalian life cycle. DNA methylation marks represent an epigenetic barrier in mammalian development that is demolished when developmental potency has to be restored and subsequently re-built with the commitment to a particular cell fate. This first occurs following fertilization, when the DNA methylation marks of the parental gametes are erased in two waves of demethylation. In the first wave, the paternal pronucleus (shown in blue) undergoes rapid demethylation in the zygote, which is followed by a passive loss of DNA methylation marks in the maternal genome (shown in red) over the subsequent cell divisions. Re-establishment of DNA methylation marks commences in the ICM of the developing embryo, which forms an epigenetic barrier (dashed line) in the developmentally more restricted epiblast. PGCs (shown in green) inherit the epigenetic signature from the epiblast, and DNA methylation is again erased on a global scale concomitant with the restoration of developmental potency. Note that DNA methylation at DMRs of imprinted genes become reset in PGCs but are protected from reprogramming in the early embryo. With further development into fully specialized gametes, DNA methylation marks are re-established and developmental potency is restricted. This epigenetic barrier (dashed line) will be demolished once more in the zygote of the next generation as part of the continuous cycle of DNA methylation reprogramming.
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RSTB20110330F1: DNA methylation reprogramming in the mammalian life cycle. DNA methylation marks represent an epigenetic barrier in mammalian development that is demolished when developmental potency has to be restored and subsequently re-built with the commitment to a particular cell fate. This first occurs following fertilization, when the DNA methylation marks of the parental gametes are erased in two waves of demethylation. In the first wave, the paternal pronucleus (shown in blue) undergoes rapid demethylation in the zygote, which is followed by a passive loss of DNA methylation marks in the maternal genome (shown in red) over the subsequent cell divisions. Re-establishment of DNA methylation marks commences in the ICM of the developing embryo, which forms an epigenetic barrier (dashed line) in the developmentally more restricted epiblast. PGCs (shown in green) inherit the epigenetic signature from the epiblast, and DNA methylation is again erased on a global scale concomitant with the restoration of developmental potency. Note that DNA methylation at DMRs of imprinted genes become reset in PGCs but are protected from reprogramming in the early embryo. With further development into fully specialized gametes, DNA methylation marks are re-established and developmental potency is restricted. This epigenetic barrier (dashed line) will be demolished once more in the zygote of the next generation as part of the continuous cycle of DNA methylation reprogramming.

Mentions: Transitions in cell fate and restoration of developmental potency are closely associated with some form of epigenetic reprogramming. Indeed, in the germline, there are two genome-wide DNA demethylation events coincident with major developmental milestones (figure 1): (i) immediately following fertilization in the zygote, and (ii) during the establishment of the primordial germ cells (PGCs), which are the direct progenitors of sperm and oocytes. It is thought that these dramatic changes in epigenetic status allow the zygote to erase the epigenetic signature inherited from the gametes (with the notable exception of parental imprints) and thereby regain developmental totipotency. Likewise, epigenetic reprogramming of PGCs is associated with restoration of developmental potential and the erasure of parental imprints. PGCs derive from the epiblast—a tissue with high developmental capacity, but also one that is characteristically directed towards somatic lineages and requires significant reprogramming to restore the germline.Figure 1.


Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers.

Seisenberger S, Peat JR, Hore TA, Santos F, Dean W, Reik W - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2013)

DNA methylation reprogramming in the mammalian life cycle. DNA methylation marks represent an epigenetic barrier in mammalian development that is demolished when developmental potency has to be restored and subsequently re-built with the commitment to a particular cell fate. This first occurs following fertilization, when the DNA methylation marks of the parental gametes are erased in two waves of demethylation. In the first wave, the paternal pronucleus (shown in blue) undergoes rapid demethylation in the zygote, which is followed by a passive loss of DNA methylation marks in the maternal genome (shown in red) over the subsequent cell divisions. Re-establishment of DNA methylation marks commences in the ICM of the developing embryo, which forms an epigenetic barrier (dashed line) in the developmentally more restricted epiblast. PGCs (shown in green) inherit the epigenetic signature from the epiblast, and DNA methylation is again erased on a global scale concomitant with the restoration of developmental potency. Note that DNA methylation at DMRs of imprinted genes become reset in PGCs but are protected from reprogramming in the early embryo. With further development into fully specialized gametes, DNA methylation marks are re-established and developmental potency is restricted. This epigenetic barrier (dashed line) will be demolished once more in the zygote of the next generation as part of the continuous cycle of DNA methylation reprogramming.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539359&req=5

RSTB20110330F1: DNA methylation reprogramming in the mammalian life cycle. DNA methylation marks represent an epigenetic barrier in mammalian development that is demolished when developmental potency has to be restored and subsequently re-built with the commitment to a particular cell fate. This first occurs following fertilization, when the DNA methylation marks of the parental gametes are erased in two waves of demethylation. In the first wave, the paternal pronucleus (shown in blue) undergoes rapid demethylation in the zygote, which is followed by a passive loss of DNA methylation marks in the maternal genome (shown in red) over the subsequent cell divisions. Re-establishment of DNA methylation marks commences in the ICM of the developing embryo, which forms an epigenetic barrier (dashed line) in the developmentally more restricted epiblast. PGCs (shown in green) inherit the epigenetic signature from the epiblast, and DNA methylation is again erased on a global scale concomitant with the restoration of developmental potency. Note that DNA methylation at DMRs of imprinted genes become reset in PGCs but are protected from reprogramming in the early embryo. With further development into fully specialized gametes, DNA methylation marks are re-established and developmental potency is restricted. This epigenetic barrier (dashed line) will be demolished once more in the zygote of the next generation as part of the continuous cycle of DNA methylation reprogramming.
Mentions: Transitions in cell fate and restoration of developmental potency are closely associated with some form of epigenetic reprogramming. Indeed, in the germline, there are two genome-wide DNA demethylation events coincident with major developmental milestones (figure 1): (i) immediately following fertilization in the zygote, and (ii) during the establishment of the primordial germ cells (PGCs), which are the direct progenitors of sperm and oocytes. It is thought that these dramatic changes in epigenetic status allow the zygote to erase the epigenetic signature inherited from the gametes (with the notable exception of parental imprints) and thereby regain developmental totipotency. Likewise, epigenetic reprogramming of PGCs is associated with restoration of developmental potential and the erasure of parental imprints. PGCs derive from the epiblast—a tissue with high developmental capacity, but also one that is characteristically directed towards somatic lineages and requires significant reprogramming to restore the germline.Figure 1.

Bottom Line: Deamination by AID, BER and passive demethylation have been implicated in reprogramming in PGCs, but the process in its entirety is still poorly understood.In this review, we discuss the dynamics of DNA methylation reprogramming in PGCs and the zygote, the mechanisms involved and the biological significance of these events.Conversely, insights into in vitro reprogramming techniques may aid our understanding of epigenetic reprogramming in the germline and supply important clues in reprogramming for therapies in regenerative medicine.

View Article: PubMed Central - PubMed

Affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK. stefanie.seisenberger@babraham.ac.uk

ABSTRACT
In mammalian development, epigenetic modifications, including DNA methylation patterns, play a crucial role in defining cell fate but also represent epigenetic barriers that restrict developmental potential. At two points in the life cycle, DNA methylation marks are reprogrammed on a global scale, concomitant with restoration of developmental potency. DNA methylation patterns are subsequently re-established with the commitment towards a distinct cell fate. This reprogramming of DNA methylation takes place firstly on fertilization in the zygote, and secondly in primordial germ cells (PGCs), which are the direct progenitors of sperm or oocyte. In each reprogramming window, a unique set of mechanisms regulates DNA methylation erasure and re-establishment. Recent advances have uncovered roles for the TET3 hydroxylase and passive demethylation, together with base excision repair (BER) and the elongator complex, in methylation erasure from the zygote. Deamination by AID, BER and passive demethylation have been implicated in reprogramming in PGCs, but the process in its entirety is still poorly understood. In this review, we discuss the dynamics of DNA methylation reprogramming in PGCs and the zygote, the mechanisms involved and the biological significance of these events. Advances in our understanding of such natural epigenetic reprogramming are beginning to aid enhancement of experimental reprogramming in which the role of potential mechanisms can be investigated in vitro. Conversely, insights into in vitro reprogramming techniques may aid our understanding of epigenetic reprogramming in the germline and supply important clues in reprogramming for therapies in regenerative medicine.

Show MeSH