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dc.contributor.authorIurlaro, Marioen
dc.contributor.authorMcInroy, Gordon Ren
dc.contributor.authorBurgess, Heather Een
dc.contributor.authorDean, Wendyen
dc.contributor.authorRaiber, Eun-Angen
dc.contributor.authorBachman, Martinen
dc.contributor.authorBeraldi, Darioen
dc.contributor.authorBalasubramanian, Shankaren
dc.contributor.authorReik, Wolfen
dc.date.accessioned2016-07-27T11:40:41Z
dc.date.available2016-07-27T11:40:41Z
dc.date.issued2016-06-29en
dc.identifier.issn1474-7596
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/256868
dc.description.abstractBackground: Genome-wide methylation of cytosine can be modulated in the presence of TET and thymine DNA glycosylase (TDG) enzymes. TET is able to oxidise 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). TDG can excise the oxidative products 5fC and 5caC, initiating base excision repair. These modified bases are stable and detectable in the genome, suggesting that they could have epigenetic functions in their own right. However, functional investigation of the genome-wide distribution of 5fC has been restricted to cell culture-based systems, while its in vivo profile remains unknown. Results: Here, we describe the first analysis of the in vivo genome-wide profile of 5fC across a range of tissues from both wild-type and Tdg-deficient E11.5 mouse embryos. Changes in the formylation profile of cytosine upon depletion of TDG suggest TET/TDG-mediated active demethylation occurs preferentially at intron-exon boundaries and reveals a major role for TDG in shaping 5fC distribution at CpG islands. Moreover, we find that active enhancer regions specifically exhibit high levels of 5fC, resulting in characteristic tissue-diagnostic patterns, which suggest a role in embryonic development. Conclusions: The tissue-specific distribution of 5fC can be regulated by the collective contribution of TET-mediated oxidation and excision by TDG. The in vivo profile of 5fC during embryonic development resembles that of embryonic stem cells, sharing key features including enrichment of 5fC in enhancer and intragenic regions. Additionally, by investigating mouse embryo 5fC profiles in a tissue-specific manner, we identify targeted enrichment at active enhancers involved in tissue development.
dc.description.sponsorshipMI is supported by the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007-2013/under REA grant agreement no. 290123. GRM was supported by Trinity College and Herchel Smith studentships. MB was supported by the CRUK PhD Training Programme in Chemical Biology and Molecular Medicine. DB is supported by funding from the Wellcome Trust and Herchel Smith. The WR lab is supported by BBSRC, MRC, the Wellcome Trust, EU EpiGeneSys and BLUEPRINT. The SB lab is supported by core funding from Cancer Research UK and a Wellcome Trust Senior Investigator Award.
dc.languageEnglishen
dc.language.isoenen
dc.publisherBioMed Central
dc.rightsAttribution 4.0 International*
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleIn vivo genome-wide profiling reveals a tissue-specific role for 5-formylcytosineen
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13059-016-1001-5.en
prism.publicationDate2016en
prism.publicationNameGenome Biologyen
prism.volume17en
dc.identifier.doi10.17863/CAM.801
datacite.cites.urlhttps://www.ncbi.nlm.nih.gov/geo/query/ acc.cgi?acc=GSE77447en
dcterms.dateAccepted2016-06-06en
rioxxterms.versionofrecord10.1186/s13059-016-1001-5en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2016-06-29en
dc.contributor.orcidBalasubramanian, Shankar [0000-0002-0281-5815]
dc.contributor.orcidReik, Wolf [0000-0003-0216-9881]
dc.identifier.eissn1474-760X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBBSRC (BB/K010859/1)
pubs.funder-project-idWellcome Trust (099232/Z/12/Z)
pubs.funder-project-idEC FP7 MC ITN (290123)


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