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Metabolic regulation of pluripotency and germ cell fate through α-ketoglutarate.

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cam.issuedOnline2018-09-26
dc.contributor.authorTischler, Julia
dc.contributor.authorGruhn, Wolfram H
dc.contributor.authorReid, John
dc.contributor.authorAllgeyer, Edward
dc.contributor.authorBuettner, Florian
dc.contributor.authorMarr, Carsten
dc.contributor.authorTheis, Fabian
dc.contributor.authorSimons, Ben D
dc.contributor.authorWernisch, Lorenz
dc.contributor.authorSurani, M Azim
dc.contributor.orcidTischler, Julia [0000-0003-4665-4141]
dc.contributor.orcidAllgeyer, Edward [0000-0002-2187-4423]
dc.contributor.orcidBuettner, Florian [0000-0001-5587-6761]
dc.contributor.orcidTheis, Fabian [0000-0002-2419-1943]
dc.contributor.orcidSurani, M Azim [0000-0002-8640-4318]
dc.date.accessioned2018-11-17T00:32:08Z
dc.date.available2018-11-17T00:32:08Z
dc.date.issued2019-01-03
dc.description.abstractAn intricate link is becoming apparent between metabolism and cellular identities. Here, we explore the basis for such a link in an in vitro model for early mouse embryonic development: from naïve pluripotency to the specification of primordial germ cells (PGCs). Using single-cell RNA-seq with statistical modelling and modulation of energy metabolism, we demonstrate a functional role for oxidative mitochondrial metabolism in naïve pluripotency. We link mitochondrial tricarboxylic acid cycle activity to IDH2-mediated production of alpha-ketoglutarate and through it, the activity of key epigenetic regulators. Accordingly, this metabolite has a role in the maintenance of naïve pluripotency as well as in PGC differentiation, likely through preserving a particular histone methylation status underlying the transient state of developmental competence for the PGC fate. We reveal a link between energy metabolism and epigenetic control of cell state transitions during a developmental trajectory towards germ cell specification, and establish a paradigm for stabilizing fleeting cellular states through metabolic modulation.
dc.description.sponsorshipJ.T. was supported by the Austrian Academy of Sciences, the Wellcome Trust, and the Swiss National Fund for Science, W.H.G. by EMBO and the Wellcome Trust, J.R. and L.W. by the UK Medical Research Council, and E.A. by the Wellcome Trust. M.A.S. is a Wellcome Senior Investigator. Work at the Gurdon Institute is supported by a core grant from the Wellcome Trust and Cancer Research UK.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.32760
dc.identifier.eissn1460-2075
dc.identifier.issn0261-4189
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285394
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.15252/embj.201899518
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectcell state transitions
dc.subjectgerm cells
dc.subjectmetabolism
dc.subjectpseudotime analysis
dc.subjectsingle‐cell analysis
dc.subjectAnimals
dc.subjectCell Differentiation
dc.subjectCells, Cultured
dc.subjectEmbryo, Mammalian
dc.subjectEmbryonic Stem Cells
dc.subjectEpigenesis, Genetic
dc.subjectFemale
dc.subjectGene Expression Regulation, Developmental
dc.subjectGerm Cells
dc.subjectKetoglutaric Acids
dc.subjectMale
dc.subjectMetabolic Networks and Pathways
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Transgenic
dc.subjectPluripotent Stem Cells
dc.titleMetabolic regulation of pluripotency and germ cell fate through α-ketoglutarate.
dc.typeArticle
dcterms.dateAccepted2018-08-27
prism.issueIdentifier1
prism.publicationDate2019
prism.publicationNameEMBO J
prism.volume38
pubs.funder-project-idWellcome Trust (096738/Z/11/Z)
pubs.funder-project-idMRC (unknown)
pubs.funder-project-idWellcome Trust (098357/Z/12/Z)
pubs.funder-project-idMedical Research Council (MC_PC_12009)
pubs.funder-project-idMedical Research Council (MR/P009948/1)
rioxxterms.licenseref.startdate2019-01
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.15252/embj.201899518

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