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Reference: la Thangue, NB, Ghari, F, Munro, S et al., Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response. Science Advances, 2 (2), e1501257.Citable link to this page:

 

Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response

Abstract: Peptidyl arginine deiminase (PAD) 4 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 identity of reader domains specifically recognising citrulline modifications remain unclear. E2F transcription factors play an important role in regulating gene expression in diverse biological processes. Here, we show that E2F-1 is citrullinated by PAD4 on functionally important arginine residues. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells, and augments binding of the bromodomain reader BRD4 to an acetylated domain in E2F-1. Accordingly, the combined inhibition of PAD4 and BRD4 suppresses cytokine gene expression, and when administered as a combination therapy in the murine collagen-induced arthritis model, provides an effective approach for preventing collagen-induced arthritis. Our results shed light on a new E2F-dependent pathway that mediates the inflammatory effect of PAD4 and, for the first time, establish the interplay between citrullination and acetylation as a regulatory interface for driving inflammatory gene expression.

Peer Review status:Peer reviewedPublication status:PublishedVersion:Accepted manuscript Funder: Medical Research Council   Funder: Cancer Research UK   Funder: Rosetrees Trust   Funder: National Institutes of Health   Funder: John Fell Fund   Funder: Wellcome Trust   Funder: European Union   Notes:Copyright © 2016, The Authors This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Bibliographic Details

Publisher: American Association for the Advancement of Science:

Publisher Website: http://www.aaas.org/

Publisher: American Association for the Advancement of Science: Science Advances

Journal: Science Advancessee more from them

Publication Website: http://advances.sciencemag.org/

pages:e1501257Identifiers

Urn: uuid:dd00ce0a-c025-4227-989d-5e337dd8637e

Source identifier: 590888

Doi: https://doi.org/10.1126/sciadv.1501257

Issn: 2375-2548 Item Description

Type: Journal article;

Version: Accepted manuscript Tiny URL: pubs:590888

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Author: la Thangue, NB - institutionUniversity of Oxford Oxford, MSD, Oncology - - - Ghari, F - institutionUniversity of Oxford Oxford, M

Source: https://ora.ox.ac.uk/objects/uuid:dd00ce0a-c025-4227-989d-5e337dd8637e



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