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Nucleic Acids Res. 2016 Aug 19;44(14):6693-706. doi: 10.1093/nar/gkw258. Epub 2016 Apr 15.

Protection of CpG islands from DNA methylation is DNA-encoded and evolutionarily conserved.

Author information

1
Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
2
Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.
3
Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
4
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK.
5
Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK rob.klose@bioch.ox.ac.uk.

Abstract

DNA methylation is a repressive epigenetic modification that covers vertebrate genomes. Regions known as CpG islands (CGIs), which are refractory to DNA methylation, are often associated with gene promoters and play central roles in gene regulation. Yet how CGIs in their normal genomic context evade the DNA methylation machinery and whether these mechanisms are evolutionarily conserved remains enigmatic. To address these fundamental questions we exploited a transchromosomic animal model and genomic approaches to understand how the hypomethylated state is formed in vivo and to discover whether mechanisms governing CGI formation are evolutionarily conserved. Strikingly, insertion of a human chromosome into mouse revealed that promoter-associated CGIs are refractory to DNA methylation regardless of host species, demonstrating that DNA sequence plays a central role in specifying the hypomethylated state through evolutionarily conserved mechanisms. In contrast, elements distal to gene promoters exhibited more variable methylation between host species, uncovering a widespread dependence on nucleotide frequency and occupancy of DNA-binding transcription factors in shaping the DNA methylation landscape away from gene promoters. This was exemplified by young CpG rich lineage-restricted repeat sequences that evaded DNA methylation in the absence of co-evolved mechanisms targeting methylation to these sequences, and species specific DNA binding events that protected against DNA methylation in CpG poor regions. Finally, transplantation of mouse chromosomal fragments into the evolutionarily distant zebrafish uncovered the existence of a mechanistically conserved and DNA-encoded logic which shapes CGI formation across vertebrate species.

PMID:
27084945
PMCID:
PMC5001583
DOI:
10.1093/nar/gkw258
[Indexed for MEDLINE]
Free PMC Article

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