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dc.contributor.authorSaunderson, EAen_US
dc.contributor.authorStepper, Pen_US
dc.contributor.authorGomm, JJen_US
dc.contributor.authorHoa, Len_US
dc.contributor.authorMorgan, Aen_US
dc.contributor.authorAllen, MDen_US
dc.contributor.authorJones, JLen_US
dc.contributor.authorGribben, JGen_US
dc.contributor.authorJurkowski, TPen_US
dc.contributor.authorFicz, Gen_US
dc.date.accessioned2017-12-08T17:48:25Z
dc.date.available2017-08-16en_US
dc.date.issued2017-11-13en_US
dc.date.submitted2017-11-23T09:11:13.483Z
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/29503
dc.description.abstractAberrant promoter DNA hypermethylation is a hallmark of cancer; however, whether this is sufficient to drive cellular transformation is not clear. To investigate this question, we use a CRISPR-dCas9 epigenetic editing tool, where an inactive form of Cas9 is fused to DNA methyltransferase effectors. Using this system, here we show simultaneous de novo DNA methylation of genes commonly methylated in cancer, CDKN2A, RASSF1, HIC1 and PTEN in primary breast cells isolated from healthy human breast tissue. We find that promoter methylation is maintained in this system, even in the absence of the fusion construct, and this prevents cells from engaging senescence arrest. Our data show that the key driver of this phenotype is repression of CDKN2A transcript p16 where myoepithelial cells harbour cancer-like gene expression but do not exhibit anchorage-independent growth. This work demonstrates that hit-and-run epigenetic events can prevent senescence entry, which may facilitate tumour initiation.en_US
dc.description.sponsorshipMRC NIRG award [Grant Ref: MR/M01892X/1] and Baden-Würtemberg Stiftung [95011370.]en_US
dc.format.extent1450 - ?en_US
dc.languageengen_US
dc.language.isoenen_US
dc.relation.ispartofNat Communen_US
dc.rightsCC BY 4.0. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.subjectBreasten_US
dc.subjectCRISPR-Cas Systemsen_US
dc.subjectCell Transformation, Neoplasticen_US
dc.subjectCells, Cultureden_US
dc.subjectCellular Senescenceen_US
dc.subjectCyclin-Dependent Kinase Inhibitor p16en_US
dc.subjectCyclin-Dependent Kinase Inhibitor p18en_US
dc.subjectDNA (Cytosine-5-)-Methyltransferasesen_US
dc.subjectDNA Methylationen_US
dc.subjectEpigenomicsen_US
dc.subjectFemaleen_US
dc.subjectGene Editingen_US
dc.subjectHumansen_US
dc.subjectKruppel-Like Transcription Factorsen_US
dc.subjectPTEN Phosphohydrolaseen_US
dc.subjectPromoter Regions, Geneticen_US
dc.subjectTumor Suppressor Proteinsen_US
dc.titleHit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors.en_US
dc.typeArticle
dc.rights.holder© The Author(s) 2017.
dc.identifier.doi10.1038/s41467-017-01078-2en_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/29133799en_US
pubs.issue1en_US
pubs.notesNo embargoen_US
pubs.publication-statusPublished onlineen_US
pubs.volume8en_US
dcterms.dateAccepted2017-08-16en_US


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