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Active and Passive Demethylation of Male and Female Pronuclear DNA in the Mammalian Zygote

ABSTRACT: The epigenomes of mammalian sperm and oocytes, characterized by gamete-specific 5-methylcytosine (5mC) patterns, are reprogrammed during early embryogenesis to establish full developmental potential. Previous studies have suggested that the paternal genome is actively demethylated in the zygote while the maternal genome undergoes subsequent passive demethylation via DNA replication during cleavage. Active demethylation is known to depend on 5mC oxidation by Tet dioxygenases and excision of oxidized bases by thymine DNA glycosylase (TDG). Here we show that both maternal and paternal genomes undergo widespread active and passive demethylation in zygotes before the first mitotic division. Passive demethylation was blocked by the replication inhibitor aphidicolin, and active demethylation was abrogated by deletion of Tet3 in both pronuclei. At actively demethylated loci, 5mCs were processed to unmodified cytosines. Surprisingly, the demethylation process was unaffected by the deletion of TDG from the zygote, suggesting the existence of other demethylation mechanisms downstream of Tet3-mediated oxidation.

ORGANISM(S): Mus musculus

PROVIDER: GSE56650 | GEO | 2014/09/11

SECONDARY ACCESSION(S): PRJNA244161

REPOSITORIES: GEO

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Active Demethylation of Both Maternal and Paternal Genomes in Mouse Zygotes

Project description:The epigenomes of mammalian sperm and oocytes, characterized by gamete-specific 5-methylcytosine (5mC) patterns, are reprogrammed in early embryogenesis to establish full developmental potential. It is broadly accepted that the paternal genome is actively demethylated in the zygote while the maternal genome undergoes passive demethylation thanks to DNA replication over the subsequent cleavage divisions. Here we reveal that both maternal and paternal genomes undergo widespread active and passive demethylation in the pronuclear zygote before the first mitotic division. Whereas the passive demethylation requires DNA replication, the active demethylation relies on enzymatic oxidation of 5mC, as deletion of the DNA dioxygenase, Tet3, but not the inhibition of replication, blocks the active demethylation. At actively demethylated loci, 5mCs appear to be processed to unmodified cytosines in a manner independent of the DNA glycosylase TDG. These observations suggest the occurrence of genuine active demethylation in both parental genomes following fertilization. An extra supportive Tet3 knock-out female pronuclear sample related to experiment Series GSE56650.

2016-09-01 | E-GEOD-60777 | biostudies-arrayexpress

Active and Passive Demethylation of Male and Female Pronuclear DNA in the Mammalian Zygote

Project description:The epigenomes of mammalian sperm and oocytes, characterized by gamete-specific 5-methylcytosine (5mC) patterns, are reprogrammed during early embryogenesis to establish full developmental potential. Previous studies have suggested that the paternal genome is actively demethylated in the zygote while the maternal genome undergoes subsequent passive demethylation via DNA replication during cleavage. Active demethylation is known to depend on 5mC oxidation by Tet dioxygenases and excision of oxidized bases by thymine DNA glycosylase (TDG). Here we show that both maternal and paternal genomes undergo widespread active and passive demethylation in zygotes before the first mitotic division. Passive demethylation was blocked by the replication inhibitor aphidicolin, and active demethylation was abrogated by deletion of Tet3 in both pronuclei. At actively demethylated loci, 5mCs were processed to unmodified cytosines. Surprisingly, the demethylation process was unaffected by the deletion of TDG from the zygote, suggesting the existence of other demethylation mechanisms downstream of Tet3-mediated oxidation. The dataset includes RRBS anlysis of 2 MII oocyte samples, 3 WT female pronuclei samples PN3-4 stage, 2 Tet3 KO female pronuclei samples and 2 Aphidicolin treated female pronuclei samples. Also as male counterpart, a Sperm sample, 2 WT male pronuclei samples PN3-4 stage, 2 Tet3 KO male pronuclei samples and 2 Aphidicolin treated male pronuclei samples were included.

2014-09-11 | E-GEOD-56650 | biostudies-arrayexpress

Active Demethylation of Both Maternal and Paternal Genomes in Mouse Zygotes

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Haploinsufficiency, but not defective paternal 5mC oxidation, accounts for the developmental defects of maternal Tet3 knockouts

Project description:DNA demethylation of paternal genome in zygotes takes place in various mammals including mice and human. Recent studies have revealed that this is achieved through Tet3-mediated iterative oxidation of 5-methylcytosine (5mC) coupled with replication-dependent dilution. Tet3-mediated paternal DNA demethylation is believed to be required for mouse development given that Tet3 heterozygous embryos, derived by fertilizing Tet3 knockout (KO) oocytes with wild-type (WT) sperms, exhibit 5mC oxidation defects and embryonic sublethality, Here we demonstrate that the sublethality phenotype of the maternal KO mice is caused by haploinsufficiency of Tet3, but not by defective paternal 5mC oxidation. We found that Tet3 heterozygous mice derived from crosses of heterozygous father or mother with WT mice also exhibit sublethality phenotype similarly to Tet3 maternal KO mice. Importantly, embryos reconstituted with WT paternal nuclei that bypassed 5mC oxidation develop to term and grow to adulthood normally. Genome-scale DNA methylation analysis of the maternal KO zygotes and blastocysts demonstrated that hypermethylation caused by the depletion of maternal Tet3 is largely diminished by the blastocyst stage. Our study thus not only demonstrates that Tet3-mediated paternal 5mC oxidation is dispensable for mouse development but also suggests the existence of a compensation mechanism in preimplantation embryos that can compensate for the defective 5mC oxidation in zygotes. This data set includes RRBS data of wild-type and maternal Tet3 KO zygotes and blastocysts (C57BL/6J x CAST/EiJ)

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2014-01-04 | E-GEOD-53809 | biostudies-arrayexpress

Roles of TET and TDG in DNA demethylation in proliferating and non-proliferating immune cells [RNA-seq]

Project description:TET enzymes mediate DNA demethylation by oxidizing 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Because these oxidized methylcytosines (oxi-mC) are not recognized by the maintenance methyltransferase DNMT1, DNA demethylation can occur through “passive”, replication-dependent dilution as cells divide. A distinct, replication-independent (“active”) mechanism of DNA demethylation involves excision of 5fC and 5caC by the DNA repair enzyme thymine DNA glycosylase (TDG), followed by base excision repair. Here we used inducible gene-disrupted mice to show that TET enzymes influence both replication-dependent primary T cell differentiation and replication-independent macrophage differentiation, whereas TDG has no effect. Mice with long-term (1 year) deletion of Tdg are healthy and show normal survival and hematopoiesis. In summary, TET enzymes regulate differentiation and DNA demethylation primarily through passive dilution of oxidized methylcytosines in replicating T cells, and active, replication-independent DNA demethylation mediated by TDG does not appear to be essential for immune cell activation or differentiation.

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Roles of TET and TDG in DNA demethylation in proliferating and non-proliferating immune cells [CMS-Seq]

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Roles of TET and TDG in DNA demethylation in proliferating and non-proliferating immune cells [BS-PB]

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Programming and inheritance of parental DNA methylomes in mammals

Project description:The reprogramming of parental methylomes is essential for embryonic development. In mammals, paternal 5-methylcytosines (5mCs) have been proposed to be actively converted to oxidized bases. These paternal oxidized bases and maternal 5mCs are believed to be passively diluted by cell divisions. By generating single-base resolution, allele-specific DNA methylomes from mouse gametes, early embryos, and primordial germ cell (PGC), as well as single-base-resolution maps of oxidized cytosine bases for early embryos, we report the existence of 5hmC and 5fC in both maternal and paternal genomes and find that 5mC or its oxidized derivatives, at the majority of demethylated CpGs, are converted to unmodified cytosines independent of passive dilution from gametes to four-cell embryos. Therefore, we conclude that paternal methylome and at least a significant proportion of maternal methylome go through active demethylation during embryonic development. Additionally, all the known imprinting control regions (ICRs) were classified into germ-line or somatic ICRs.

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Role of Tet3 and DNA replication in zygotic demethylation of both paternal and maternal genomes [RRBS]

Project description:With the exception of imprinted genes and certain repeats, DNA methylation is globally erased during pre-implantation development. Recent studies have suggested that Tet3-mediated oxidation of 5-methylcytosine (5mC) and DNA replication-dependent dilution both contribute to global paternal DNA demethylation, but demethylation of the maternal genome occurs via replication. Here we present genome-scale DNA methylation maps for both the paternal and maternal genomes of Tet3-depleted and/or DNA replication-inhibited zygotes. In both genomes, we found that inhibition of DNA replication blocks DNA demethylation independently from Tet3 function, and that Tet3 facilitates DNA demethylation by coupling with DNA replication. For both, our data indicate that replication-dependent dilution is the major contributor to demethylation, but Tet3 plays an important role, particularly at certain loci. Our study therefore both defines the respective functions of Tet3 and DNA replication in paternal DNA demethylation and reveals an unexpected contribution of Tet3 to demethylation of the maternal genome. In this data set, we include RRBS data of manually isolated paternal and maternal pronuclei from both WT and Tet3 CKO zygotes with or without aphidicolin treatment

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