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dc.contributor.authorGhari, Fatemeh
dc.contributor.authorQuirke, Anne-Marie
dc.contributor.authorMunro, Shonagh
dc.contributor.authorKawalkowska, Joanna
dc.contributor.authorPicaud, Sarah
dc.contributor.authorMcGouran, Joanna
dc.contributor.authorSubramanian, Venkataraman
dc.contributor.authorMuth, Aaron
dc.contributor.authorWilliams, Richard
dc.contributor.authorKessler, Benedikt
dc.contributor.authorThompson, Paul R
dc.contributor.authorFillipakopoulos, Panagis
dc.contributor.authorKnapp, Stefan
dc.contributor.authorVenables, Patrick J.
dc.contributor.authorLa Thangue, Nicholas B.
dc.date2022-08-11T08:11:00.000
dc.date.accessioned2022-08-23T17:28:01Z
dc.date.available2022-08-23T17:28:01Z
dc.date.issued2016-02-05
dc.date.submitted2017-03-15
dc.identifier.citationSci Adv. 2016 Feb 5;2(2):e1501257. doi: 10.1126/sciadv.1501257. eCollection 2016. <a href="http://advances.sciencemag.org/content/2/2/e1501257">Link to article on publisher's website</a>
dc.identifier.doi10.1126/sciadv.1501257
dc.identifier.pmid26989780
dc.identifier.urihttp://hdl.handle.net/20.500.14038/49993
dc.description.abstractPeptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to an acetylated domain in E2F-1, and PAD4 and BRD4 coexist with E2F-1 on cytokine gene promoters. Accordingly, the combined inhibition of PAD4 and BRD4 disrupts the chromatin-bound complex and suppresses cytokine gene expression. In the murine collagen-induced arthritis model, chromatin-bound E2F-1 in inflammatory cells and consequent cytokine expression are diminished upon small-molecule inhibition of PAD4 and BRD4, and the combined treatment is clinically efficacious in preventing disease progression. Our results shed light on a new transcription-based mechanism that mediates the inflammatory effect of PAD4 and establish the interplay between citrullination and acetylation in the control of E2F-1 as a regulatory interface for driving inflammatory gene expression.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=26989780&dopt=Abstract">Link to article in PubMed</a>
dc.relation.urlhttps://ora.ox.ac.uk/objects/uuid:dd00ce0a-c025-4227-989d-5e337dd8637e
dc.rightsCopyright © 2016, The Authors.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBRD4
dc.subjectE2F-1
dc.subjectPAD4
dc.subjectcancer
dc.subjectcitrullination
dc.subjectimmune response
dc.subjectinflammation
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectTherapeutics
dc.titleCitrullination-acetylation interplay guides E2F-1 activity during the inflammatory response
dc.typeJournal Article
dc.source.journaltitleScience Advances
dc.source.volume2
dc.source.issue2
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1114&amp;context=thompson&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/thompson/112
dc.identifier.contextkey9860355
refterms.dateFOA2022-08-23T17:28:01Z
html.description.abstract<p>Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to an acetylated domain in E2F-1, and PAD4 and BRD4 coexist with E2F-1 on cytokine gene promoters. Accordingly, the combined inhibition of PAD4 and BRD4 disrupts the chromatin-bound complex and suppresses cytokine gene expression. In the murine collagen-induced arthritis model, chromatin-bound E2F-1 in inflammatory cells and consequent cytokine expression are diminished upon small-molecule inhibition of PAD4 and BRD4, and the combined treatment is clinically efficacious in preventing disease progression. Our results shed light on a new transcription-based mechanism that mediates the inflammatory effect of PAD4 and establish the interplay between citrullination and acetylation in the control of E2F-1 as a regulatory interface for driving inflammatory gene expression.</p>
dc.identifier.submissionpaththompson/112
dc.contributor.departmentThompson Lab
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pagese1501257


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Copyright © 2016, The Authors.
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