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

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