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Sci Adv. 2016 Feb 5;2(2):e1501257. doi: 10.1126/sciadv.1501257. eCollection 2016 Feb.

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

Author information

1
Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
2
Kennedy Institute, University of Oxford, Oxford OX3 7DQ, UK.
3
Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
4
University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
5
Ludwig Institute, University of Oxford, Oxford OX3 7DQ, UK.
6
Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.; Target Discovery Institute, University of Oxford, Oxford OX3 7DQ, UK.

Abstract

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.

KEYWORDS:

BRD4; E2F-1; PAD4; cancer; citrullination; immune response; inflammation

PMID:
26989780
PMCID:
PMC4788482
DOI:
10.1126/sciadv.1501257
[Indexed for MEDLINE]
Free PMC Article

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