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Epigenetic inheritance is unfaithful at intermediately methylated CpG sites.

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Gebert, Daniel 
Takahashi, Nozomi 


DNA methylation at the CpG dinucleotide is considered a stable epigenetic mark due to its presumed long-term inheritance through clonal expansion. Here, we perform high-throughput bisulfite sequencing on clonally derived somatic cell lines to quantitatively measure methylation inheritance at the nucleotide level. We find that although DNA methylation is generally faithfully maintained at hypo- and hypermethylated sites, this is not the case at intermediately methylated CpGs. Low fidelity intermediate methylation is interspersed throughout the genome and within genes with no or low transcriptional activity, and is not coordinately maintained between neighbouring sites. We determine that the probabilistic changes that occur at intermediately methylated sites are likely due to DNMT1 rather than DNMT3A/3B activity. The observed lack of clonal inheritance at intermediately methylated sites challenges the current epigenetic inheritance model and has direct implications for both the functional relevance and general interpretability of DNA methylation as a stable epigenetic mark.



Base Sequence, Nucleotides, DNA Methylation, Cell Line, Epigenesis, Genetic

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Nat Commun

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Springer Science and Business Media LLC
Human Frontier Science Program (HFSP) (CDA00032/2018-C)
Wellcome Trust (206257/Z/17/Z)
Wellcome Trust (210757/Z/18/Z)
Medical Research Council (MR/R009791/1)
Cambridge Trust International Studentship; Postdoctoral Fellowship from the Deutsche Forschungsgemeinschaft