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dc.contributor.authorTakashima, Yasuhiroen
dc.contributor.authorGuo, Geen
dc.contributor.authorLoos, Remcoen
dc.contributor.authorNichols, Jenniferen
dc.contributor.authorFicz, Gabriellaen
dc.contributor.authorKrueger, Felixen
dc.contributor.authorOxley, Daviden
dc.contributor.authorSantos, Fatimaen
dc.contributor.authorClarke, Jamesen
dc.contributor.authorMansfield, Williamen
dc.contributor.authorReik, Wolfen
dc.contributor.authorBertone, Paulen
dc.contributor.authorSmith, Austinen
dc.date.accessioned2018-11-29T00:30:31Z
dc.date.available2018-11-29T00:30:31Z
dc.date.issued2014-09en
dc.identifier.issn0092-8674
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286042
dc.description.abstractCurrent human pluripotent stem cells lack the transcription factor circuitry that governs the ground state of mouse embryonic stem cells (ESC). Here, we report that short-term expression of two components, NANOG and KLF2, is sufficient to ignite other elements of the network and reset the human pluripotent state. Inhibition of ERK and protein kinase C sustains a transgene-independent rewired state. Reset cells self-renew continuously without ERK signaling, are phenotypically stable, and are karyotypically intact. They differentiate in vitro and form teratomas in vivo. Metabolism is reprogrammed with activation of mitochondrial respiration as in ESC. DNA methylation is dramatically reduced and transcriptome state is globally realigned across multiple cell lines. Depletion of ground-state transcription factors, TFCP2L1 or KLF4, has marginal impact on conventional human pluripotent stem cells but collapses the reset state. These findings demonstrate feasibility of installing and propagating functional control circuitry for ground-state pluripotency in human cells.
dc.description.sponsorshipThis research was supported by the UK Medical Research Council, the Japan Science and Technology agency (JST, PRESTO), the Genome Biology Unit of the European Molecular Biology Laboratory, European Commission projects PluriMes, BetaCellTherapy, EpiGeneSys, and Blueprint, and the Wellcome Trust. Y.T. was a University of Cambridge Herchel Smith Fellow. A.S. is a Medical Research Council Professor.
dc.format.mediumPrinten
dc.languageengen
dc.publisherElsevier (Cell Press)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMitochondriaen
dc.subjectPluripotent Stem Cellsen
dc.subjectAnimalsen
dc.subjectHumansen
dc.subjectMiceen
dc.subjectHomeodomain Proteinsen
dc.subjectTranscription Factorsen
dc.subjectCytological Techniquesen
dc.subjectEpigenesis, Geneticen
dc.subjectKruppel-Like Transcription Factorsen
dc.subjectEmbryonic Stem Cellsen
dc.subjectTranscriptomeen
dc.subjectNanog Homeobox Proteinen
dc.titleResetting transcription factor control circuitry toward ground-state pluripotency in human.en
dc.typeArticle
prism.endingPage1269
prism.issueIdentifier6en
prism.publicationDate2014en
prism.publicationNameCellen
prism.startingPage1254
prism.volume158en
dc.identifier.doi10.17863/CAM.33360
dcterms.dateAccepted2014-08-22en
rioxxterms.versionofrecord10.1016/j.cell.2014.08.029en
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2014-09en
dc.contributor.orcidLoos, Remco [0000-0002-9850-6821]
dc.contributor.orcidNichols, Jennifer [0000-0002-8650-1388]
dc.contributor.orcidFicz, Gabriella [0000-0001-9313-9578]
dc.contributor.orcidKrueger, Felix [0000-0002-5513-3324]
dc.contributor.orcidSantos, Fatima [0000-0002-3854-4084]
dc.contributor.orcidReik, Wolf [0000-0003-0216-9881]
dc.contributor.orcidBertone, Paul [0000-0001-5059-4829]
dc.contributor.orcidSmith, Austin [0000-0002-3029-4682]
dc.identifier.eissn1097-4172
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (G1001028)
pubs.funder-project-idJapan Science and Technology Agency (JST) (unknown)
pubs.funder-project-idMRC (G1100526)
pubs.funder-project-idMRC (MC_PC_12009)


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