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DNA G-quadruplex structures mould the DNA methylome

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Balasubramanian, Shankar  ORCID logo
Mao, Shiqing 
Ghanbarian, Avazeh 
Martinez Cuesta, Sergio  ORCID logo


Control of DNA methylation level is critical for gene regulation, and the factors that govern hypomethylation at CpG islands (CGIs) are still being uncovered. Here, we provide evidence that G-quadruplex (G4) DNA secondary structures are genomic features that influence methylation at CGIs. We show that the presence of G4 structure is tightly associated with CGI hypomethylation in the human genome. Surprisingly, we find that these G4 sites are enriched for DNA methyltransferase 1 (DNMT1) occupancy, which is consistent with our biophysical observations that DNMT1 exhibits higher binding affinity for G4s as compared to duplex, hemi-methylated or single-stranded DNA. The biochemical assays also show that the G4 structure itself, rather than sequence, inhibits DNMT1 enzymatic activity. Based on these data, we propose that G4 formation sequesters DNMT1 thereby protecting certain CGIs from methylation and inhibiting local methylation.



CpG Islands, DNA, DNA Methylation, Epigenomics, G-Quadruplexes, Gene Expression Regulation, Genome, Human, Humans, K562 Cells, Monte Carlo Method, Nucleic Acid Conformation, Promoter Regions, Genetic

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Nature Structural and Molecular Biology

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Springer Nature
Wellcome Trust (099232/Z/12/Z)
Cancer Research UK (CB4330)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (747297)
This work is supported by a core CRUK award (C14303/A17197). S.B. is a Senior Investigator of the Wellcome Trust (grant no. 099232/z/12/z). JS is a Marie Curie Fellow of the European Union (747297-QAPs-H2020-MSCA-IF-2016).