Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by Aid deficiency
By C. Popp, W. Dean, Suhua Feng, Shawn Cokus, Simon R. Andrews, Matteo Pellegrini, Steven E. Jacobsen, Wolf Reik. Nature, 2010
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Epigenetic reprogramming including demethylation of DNA occurs in mammalian primordial germ cells (PGCs) and in early embryos, and is important for the erasure of imprints and epimutations, and the return to pluripotency. The extent of this reprogramming and its molecular mechanisms are poorly understood. We previously showed that the cytidine deaminases AID and APOBEC1 can deaminate 5-methylcytosine in vitro and in Escherichia coli, and in the mouse are expressed in tissues in which demethylation occurs. Here we profiled DNA methylation throughout the genome by unbiased bisulphite next generation sequencing in wild-type and AID-deficient mouse PGCs at embryonic day (E)13.5. Wild-type PGCs revealed marked genome-wide erasure of methylation to a level below that of methylation deficient (Np95-/-, also called Uhrf1-/-) embryonic stem cells, with female PGCs being less methylated than male ones. By contrast, AID-deficient PGCs were up to three times more methylated than wild-type ones; this substantial difference occurred throughout the genome, with introns, intergenic regions and transposons being relatively more methylated than exons. Relative hypermethylation in AID-deficient PGCs was confirmed by analysis of individual loci in the genome. Our results reveal that erasure of DNA methylation in the germ line is a global process, hence limiting the potential for transgenerational epigenetic inheritance. AID deficiency interferes with genome-wide erasure of DNA methylation patterns, indicating that AID has a critical function in epigenetic reprogramming and potentially in restricting the inheritance of epimutations in mammals.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/e85b6df125acaefff8212d917bad80cb3d36517d
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Citations in the corpus
- R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters (2012, positive): “The AID cytosine deaminase, a leading contender for initiating DNA demethylation (Popp et al., 2010), requires ssDNA substrates and targets transcribed loci, including R loop-forming regions (Chaudhuri et al.”
- Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, neutral): “, 2008), mouse PGCs (Popp et al., 2010), mouse ESC/human fibroblast fused heterokaryons (Bhutani et al.”
- DNA Demethylation Dynamics (2011, background): “Independently, DNA repair by the BER pathway has been reported by other investigators to occur in PGCs (Hajkova et al., 2010).”
- Dynamic CpG island methylation landscape in oocytes and preimplantation embryos (2011, background): “Notably, the CGIs remaining methylated (≥75%) in Dnmt3L −/− oocytes were also highly methylated in Dnmt3a −/− oocytes, sperm and day 5 oocytes, suggesting that they are incompletely demethylated during primordial germ-cell reprogrammin”
- Thymine DNA Glycosylase Is Essential for Active DNA Demethylation by Linked Deamination-Base Excision Repair (2011, neutral): “, 2010) and erasure of DNA methylation at imprinted and other loci in PGCs (Popp et al., 2010), as well as with the role of GADD45a (Barreto et al.”
- DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos (2014, background): “The mature sperm genome shows 80%–90% overall CpG methylation, the highest global DNA methylation level of any cell in the mouse (Popp et al. 2010), yet the paternal genome is apparently completely demethylated shortly after zygote formation (Fig.”
- Targets and dynamics of promoter DNA methylation during early mouse development (2010, neutral): “Methods combining bisulfite treatment with deep sequencing provide information at single-nucleotide resolution, yet they require enormous sequencing efforts to give information at individual sequence”
- Uncovering the role of 5-hydroxymethylcytosine in the epigenome (2011, background): “Indeed, AID contributes to DNA demethylation in PGC”
- Somatic cell reprogramming and transitions between pluripotent states: facts, hypotheses, unresolved issues (2010, neutral): “In addition, it has been suggested that global demethylation of the genome in primordial germ cells may also occur by an active mechanism involving methyl-cytosine deamination by AID (activation-induced cytidine deaminase) (Popp et al., 2010).”
- Child health, developmental plasticity, and epigenetic programming. (2011, background): “(96), Ray-Gallet and Almouzni (97), and Xu et al.”