TY - JOUR A1 - Ghari, Fatemeh A1 - Quirke, Anne-Marie A1 - Munro, Shonagh A1 - Kawalkowska, Joanna A1 - Picaud, Sarah A1 - McGouran, Joanna A1 - Subramanian, Venkataraman A1 - Muth, Aaron A1 - Williams, Richard A1 - Kessler, Benedikt A1 - Thompson, Paul Richard A1 - Fillipakopoulos, Panagis A1 - Knapp, Stefan A1 - Venables, Patrick J. A1 - La Thangue, Nicholas B. T1 - Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response T2 - Science advances N2 - 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. KW - E2F-1 KW - PAD4 KW - BRD4 KW - citrullination KW - cancer KW - immune response KW - inflammation Y1 - 2016 UR - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/42257 UR - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-422579 UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788482 UR - http://advances.sciencemag.org/content/2/2/e1501257 SN - 2375-2548 N1 - 2016 © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. Distributed under a Creative Commons Attribution License 4.0 (CC BY). VL - 2 IS - 2, e1501257 SP - 1 EP - 10 PB - American Association for the Advancement of Science CY - Washington, DC [u. a.] ER -