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dc.contributor.authorHolik, AZ
dc.contributor.authorYoung, M
dc.contributor.authorKrzystyniak, J
dc.contributor.authorWilliams, GT
dc.contributor.authorMetzger, D
dc.contributor.authorShorning, BY
dc.contributor.authorClarke, AR
dc.date.accessioned2020-12-17T03:34:48Z
dc.date.available2020-12-17T03:34:48Z
dc.date.issued2014-07-01
dc.identifierpii: PGENETICS-D-14-00086
dc.identifier.citationHolik, A. Z., Young, M., Krzystyniak, J., Williams, G. T., Metzger, D., Shorning, B. Y. & Clarke, A. R. (2014). Brg1 Loss Attenuates Aberrant Wnt-Signalling and Prevents Wnt-Dependent Tumourigenesis in the Murine Small Intestine. PLOS GENETICS, 10 (7), https://doi.org/10.1371/journal.pgen.1004453.
dc.identifier.issn1553-7404
dc.identifier.urihttp://hdl.handle.net/11343/254943
dc.description.abstractTumourigenesis within the intestine is potently driven by deregulation of the Wnt pathway, a process epigenetically regulated by the chromatin remodelling factor Brg1. We aimed to investigate this interdependency in an in vivo setting and assess the viability of Brg1 as a potential therapeutic target. Using a range of transgenic approaches, we deleted Brg1 in the context of Wnt-activated murine small intestinal epithelium. Pan-epithelial loss of Brg1 using VillinCreERT2 and AhCreERT transgenes attenuated expression of Wnt target genes, including a subset of stem cell-specific genes and suppressed Wnt-driven tumourigenesis improving animal survival. A similar increase in survival was observed when Wnt activation and Brg1 loss were restricted to the Lgr5 expressing intestinal stem cell population. We propose a mechanism whereby Brg1 function is required for aberrant Wnt signalling and ultimately for the maintenance of the tumour initiating cell compartment, such that loss of Brg1 in an Apc-deficient context suppresses adenoma formation. Our results highlight potential therapeutic value of targeting Brg1 and serve as a proof of concept that targeting the cells of origin of cancer may be of therapeutic relevance.
dc.languageEnglish
dc.publisherPUBLIC LIBRARY SCIENCE
dc.titleBrg1 Loss Attenuates Aberrant Wnt-Signalling and Prevents Wnt-Dependent Tumourigenesis in the Murine Small Intestine
dc.typeJournal Article
dc.identifier.doi10.1371/journal.pgen.1004453
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.source.titlePLoS Genetics
melbourne.source.volume10
melbourne.source.issue7
dc.rights.licenseCC BY
melbourne.elementsid1230373
melbourne.contributor.authorHOLIK, ALIAKSEI
dc.identifier.eissn1553-7404
melbourne.accessrightsOpen Access


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