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dc.contributor.authorChristophorou, Maria Aen
dc.contributor.authorCastelo-Branco, Gonçaloen
dc.contributor.authorHalley-Stott, Richard Pen
dc.contributor.authorOliveira, Clara Sladeen
dc.contributor.authorLoos, Remcoen
dc.contributor.authorRadzisheuskaya, Aliaksandraen
dc.contributor.authorMowen, Kerri Aen
dc.contributor.authorBertone, Paulen
dc.contributor.authorRebelo Da Silva, Joseen
dc.contributor.authorZernicka-Goetz, Magdalenaen
dc.contributor.authorNielsen, Michael Len
dc.contributor.authorGurdon, Johnen
dc.contributor.authorKouzarides, Tonyen
dc.date.accessioned2016-03-17T10:01:15Z
dc.date.available2016-03-17T10:01:15Z
dc.date.issued2014-01-26en
dc.identifier.citationChristophorou et al. Nature (2014), 507, pp. 104–108. doi: 10.1038/nature12942en
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/254537
dc.description.abstractCitrullination is the post-translational conversion of an arginine residue within a protein to the non-coded amino acid citrulline [1] . This modification leads to the loss of a positive charge and reduction in hydrogen bonding ability. It is carried out by a small family of tissue-specific vertebrate enzymes called peptidylarginine deiminases (PADIs) [2] and is associated with the development of diverse pathological states such as autoimmunity, cancer, neurodegenerative disorders, prion diseases and thrombosis [2,3] . Nonetheless, the physiological functions of citrullination remain ill-defined, though citrullination of core histones has been linked to transcriptional regulation and the DNA damage response [4-8] . PADI4 (or PAD4/PADV), the only PADI with a nuclear localization signal [9] , was previously shown to act in myeloid cells where it mediates profound chromatin decondensation during the innate immune response to infection [10]. Here we show that the expression and enzymatic activity of PADI4 are also induced under conditions of ground state pluripotency and during reprogramming. PADI4 is part of the pluripotency transcriptional network, binding to regulatory elements of key stem cell genes and activating their expression. Its inhibition lowers the percentage of pluripotent cells in the early mouse embryo and significantly reduces reprogramming efficiency. Using an unbiased proteomic approach we identify linker histone H1 variants, which are involved in the generation of compact chromatin [11], as novel PADI4 substrates. Citrullination of a single arginine residue within the DNA binding site of H1 results in its displacement from chromatin and global chromatin decondensation. Together, these results uncover a role for citrullination in the regulation of pluripotency and provide new mechanistic insights into how citrullination regulates chromatin compaction.
dc.description.sponsorshipCancer Research UK
dc.languageEnglishen
dc.language.isoenen
dc.publisherNature Publishing Group
dc.titleCitrullination regulates pluripotency and histone H1 binding to chromatinen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from the Nature Publishing Group via http://dx.doi.org/10.1038/nature12942en
prism.endingPage108
prism.publicationDate2014en
prism.publicationNameNatureen
prism.startingPage104
prism.volume507en
dc.rioxxterms.funderCRUK
dcterms.dateAccepted2013-12-06en
rioxxterms.versionofrecord10.1038/nature12942en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2014-01-26en
dc.contributor.orcidBertone, Paul [0000-0001-5059-4829]
dc.contributor.orcidRebelo Da Silva, Jose [0000-0001-5487-1117]
dc.contributor.orcidZernicka-Goetz, Magdalena [0000-0002-7004-2471]
dc.contributor.orcidGurdon, John [0000-0002-5621-3799]
dc.contributor.orcidKouzarides, Tony [0000-0002-8918-4162]
dc.identifier.eissn1476-4687
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (G1001690)
pubs.funder-project-idWellcome Trust (101861/Z/13/Z)
pubs.funder-project-idWellcome Trust (101050/Z/13/Z)
pubs.funder-project-idWellcome Trust (092096/Z/10/Z)


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