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CTCF maintains regulatory homeostasis of cancer pathways.

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cam.issuedOnline2018-08-07
dc.contributor.authorAitken, Sarah J
dc.contributor.authorIbarra-Soria, Ximena
dc.contributor.authorKentepozidou, Elissavet
dc.contributor.authorFlicek, Paul
dc.contributor.authorFeig, Christine
dc.contributor.authorMarioni, John C
dc.contributor.authorOdom, Duncan T
dc.contributor.orcidOdom, Duncan T [0000-0001-6201-5599]
dc.date.accessioned2018-09-20T12:07:14Z
dc.date.available2018-09-20T12:07:14Z
dc.date.issued2018-08-07
dc.description.abstractBACKGROUND: CTCF binding to DNA helps partition the mammalian genome into discrete structural and regulatory domains. Complete removal of CTCF from mammalian cells causes catastrophic genome dysregulation, likely due to widespread collapse of 3D chromatin looping and alterations to inter- and intra-TAD interactions within the nucleus. In contrast, Ctcf hemizygous mice with lifelong reduction of CTCF expression are viable, albeit with increased cancer incidence. Here, we exploit chronic Ctcf hemizygosity to reveal its homeostatic roles in maintaining genome function and integrity. RESULTS: We find that Ctcf hemizygous cells show modest but robust changes in almost a thousand sites of genomic CTCF occupancy; these are enriched for lower affinity binding events with weaker evolutionary conservation across the mouse lineage. Furthermore, we observe dysregulation of the expression of several hundred genes, which are concentrated in cancer-related pathways, and are caused by changes in transcriptional regulation. Chromatin structure is preserved but some loop interactions are destabilized; these are often found around differentially expressed genes and their enhancers. Importantly, the transcriptional alterations identified in vitro are recapitulated in mouse tumors and also in human cancers. CONCLUSIONS: This multi-dimensional genomic and epigenomic profiling of a Ctcf hemizygous mouse model system shows that chronic depletion of CTCF dysregulates steady-state gene expression by subtly altering transcriptional regulation, changes which can also be observed in primary tumors.
dc.description.sponsorshipThis work was supported by Cancer Research UK (SJA, XIS, CF, JCM, DTO: 20412), the Wellcome Trust (SJA: 106563/Z/14; XIS: 108438/Z/15 to JCM; SJA, XIS, CF, DTO: 202878/A/16/Z; 108749/Z/15/Z and 202878/B/16/Z to PF), Pathological Society of Great Britain & Ireland (SJA: SGS 2015/04/04), the European Research Council (CF, DTO: 615584) and the European Molecular Biology Laboratory (EK, PF, JCM).
dc.format.mediumElectronic
dc.identifier.doi10.17863/CAM.27920
dc.identifier.eissn1474-760X
dc.identifier.issn1474-7596
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/280552
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1186/s13059-018-1484-3
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCTCF
dc.subjectCancer
dc.subjectChromatin architecture
dc.subjectChromatin state
dc.subjectHemizygosity
dc.subjectTranscription
dc.subjectAnimals
dc.subjectBreast Neoplasms
dc.subjectCCCTC-Binding Factor
dc.subjectCell Line
dc.subjectChromatin
dc.subjectDNA, Neoplasm
dc.subjectEnhancer Elements, Genetic
dc.subjectFemale
dc.subjectFibroblasts
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectGenome
dc.subjectHemizygote
dc.subjectHomeostasis
dc.subjectHumans
dc.subjectLiver Neoplasms, Experimental
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Transgenic
dc.subjectProtein Binding
dc.subjectSignal Transduction
dc.subjectUterine Neoplasms
dc.titleCTCF maintains regulatory homeostasis of cancer pathways.
dc.typeArticle
dcterms.dateAccepted2018-07-16
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameGenome Biol
prism.startingPage106
prism.volume19
pubs.funder-project-idWellcome Trust (106563/Z/14/Z)
pubs.funder-project-idCancer Research UK (C14303/A17197)
pubs.funder-project-idCancer Research UK (C14303/A17197)
pubs.funder-project-idWellcome Trust (108438/E/15/Z)
pubs.funder-project-idEuropean Research Council (615584)
pubs.funder-project-idPathological Society of Great Britain & Ireland (SGS 2015/04/04)
pubs.funder-project-idCancer Research UK (22398)
pubs.funder-project-idCancer Research UK (20412)
pubs.funder-project-idWellcome Trust (202878/Z/16/Z)
rioxxterms.licenseref.startdate2018-08-07
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1186/s13059-018-1484-3

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