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dc.contributor.authorLong, Hannah K
dc.contributor.authorKing, Hamish W
dc.contributor.authorPatient, Roger K
dc.contributor.authorOdom, Duncan
dc.contributor.authorKlose, Robert J
dc.date.accessioned2018-09-08T06:33:42Z
dc.date.available2018-09-08T06:33:42Z
dc.date.issued2016-08-19
dc.identifier.issn0305-1048
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/279889
dc.description.abstractDNA 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.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherOxford University Press (OUP)
dc.rightsAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCell Line
dc.subjectChromosomes, Human, Pair 21
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice, Transgenic
dc.subjectVertebrates
dc.subjectHumans
dc.subjectTranscription Factors
dc.subjectDNA
dc.subjectEvolution, Molecular
dc.subjectSpecies Specificity
dc.subjectDNA Methylation
dc.subjectGene Expression Regulation
dc.subjectCpG Islands
dc.subjectRepetitive Sequences, Nucleic Acid
dc.subjectConserved Sequence
dc.subjectProtein Binding
dc.subjectFemale
dc.subjectMale
dc.subjectPromoter Regions, Genetic
dc.titleProtection of CpG islands from DNA methylation is DNA-encoded and evolutionarily conserved.
dc.typeArticle
prism.endingPage6706
prism.issueIdentifier14
prism.publicationDate2016
prism.publicationNameNucleic Acids Res
prism.startingPage6693
prism.volume44
dc.identifier.doi10.17863/CAM.27257
dcterms.dateAccepted2016-04-01
rioxxterms.versionofrecord10.1093/nar/gkw258
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2016-08
dc.contributor.orcidLong, Hannah K [0000-0002-5694-0398]
dc.contributor.orcidOdom, Duncan [0000-0001-6201-5599]
dc.identifier.eissn1362-4962
rioxxterms.typeJournal Article/Review
cam.issuedOnline2016-04-15


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)