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.
Highlights
Mammalian development begins with the totipotent zygote, which has the developmental potential to generate an entire organism
A direct DNA demethylase that is capable of cleaving the carbon–carbon bond between the methylgroup and the deoxyribose of the cytosine (C) has not been identified in mammals, but recent work has explored indirect demethylation pathways that involve deamination or oxidation of 5mC potentially coupled with base excision repair (BER; figure 2)
primordial germ cells (PGCs) first arise around E7.25 in the epiblast of the developing embryo [10] and, at these early stages, seem to inherit the epigenetic traits that are present in the cells of the epiblast at this time, including significant levels of global DNA methylation [11,12]
Summary
Mammalian development begins with the totipotent zygote, which has the developmental potential to generate an entire organism. Epigenetic marks, including 5mC, provide an epigenetic barrier that reduces developmental potential while promoting distinct cellular identity. This identity is stably inherited from one cell division to the through the DNA methylation maintenance machinery. A direct DNA demethylase that is capable of cleaving the carbon–carbon bond between the methylgroup and the deoxyribose of the cytosine (C) has not been identified in mammals, but recent work has explored indirect demethylation pathways that involve deamination or oxidation of 5mC potentially coupled with base excision repair (BER; figure 2). We review novel insights into how DNA methylation is reprogrammed in the mouse germline and speculate on its purpose
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