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dc.contributor.authorKang, Jinsuken
dc.contributor.authorLienhard, Matthiasen
dc.contributor.authorPastor, William Aen
dc.contributor.authorChawla, Ashuen
dc.contributor.authorNovotny, Marken
dc.contributor.authorTsagaratou, Agelikien
dc.contributor.authorLasken, Roger Sen
dc.contributor.authorThompson, Elizabeth Cen
dc.contributor.authorSurani, Azimen
dc.contributor.authorKoralov, Sergei Ben
dc.contributor.authorKalantry, Sundeepen
dc.contributor.authorChavez, Lukasen
dc.contributor.authorRao, Anjanaen
dc.date.accessioned2015-09-15T11:38:27Z
dc.date.available2015-09-15T11:38:27Z
dc.date.issued2015-07-21en
dc.identifier.citationPNAS 2015, 112(31), E4236-E4245. doi:10.1073/pnas.1510510112en
dc.identifier.issn0027-8424
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/250574
dc.description.abstractDioxygenases of the TET (Ten-Eleven Translocation) family produce oxidized methylcytosines, intermediates in DNA demethylation, as well as new epigenetic marks. Here we show data suggesting that TET proteins maintain the consistency of gene transcription. Embryos lacking Tet1 and Tet3 (Tet1/3 DKO) displayed a strong loss of 5-hydroxymethylcytosine (5hmC) and a concurrent increase in 5-methylcytosine (5mC) at the eight-cell stage. Single cells from eight-cell embryos and individual embryonic day 3.5 blastocysts showed unexpectedly variable gene expression compared with controls, and this variability correlated in blastocysts with variably increased 5mC/5hmC in gene bodies and repetitive elements. Despite the variability, genes encoding regulators of cholesterol biosynthesis were reproducibly down-regulated in Tet1/3 DKO blastocysts, resulting in a characteristic phenotype of holoprosencephaly in the few embryos that survived to later stages. Thus, TET enzymes and DNA cytosine modifications could directly or indirectly modulate transcriptional noise, resulting in the selective susceptibility of certain intracellular pathways to regulation by TET proteins.
dc.description.sponsorshipJ.K. was supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. W.A.P. was supported by the National Science Foundation predoctoral graduate research fellowship while this work was being performed, and subsequently by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. L.C. was the recipient of a Feodor-Lynen fellowship from the Alexander von Humboldt foundation. M.L. is supported by the Max Planck Society within its International Max Planck Research School for Computational Biology and Scientific Computing program (IMPRS-CBSC). A.T. was the recipient of an Irvington postdoctoral fellowship from the Cancer Research Institute. This work was supported by NIH R01 Grants AI044432 and HD065812 (to A.R.) and a Director’s New Innovator Award (DP2-OD-008646-01) (to S.K.).
dc.languageEnglishen
dc.language.isoenen
dc.publisherNational Academy of Sciences
dc.subject5-hydroxymethylcytosineen
dc.subject5hmCen
dc.subjectDNA methylationen
dc.subjectTET methylcytosine oxidasesen
dc.subjectcholesterol biosynthesisen
dc.titleSimultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis.en
dc.title.alternativeSimultaneous deletion of Tet1 and Tet3 increases transcriptome variability in early embryogenesisen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from The National Academy of Sciences via http://dx.doi.org/10.1073/pnas.1510510112en
prism.endingPageE4245
prism.publicationDate2015en
prism.publicationNamePNASen
prism.startingPageE4236
prism.volume112en
dc.rioxxterms.funderNSF
dc.rioxxterms.funderNIH
dc.rioxxterms.projectidAI044432
dc.rioxxterms.projectidHD065812
rioxxterms.versionofrecord10.1073/pnas.1510510112en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-07-21en
dc.contributor.orcidSurani, Azim [0000-0002-8640-4318]
dc.identifier.eissn1091-6490
rioxxterms.typeJournal Article/Reviewen
rioxxterms.freetoread.startdate2016-01-21


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