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

Area of Science:

• Molecular Biology
• Immunology
• Epigenetics

Background:

• Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme implicated in inflammatory diseases and cancer, but its mechanism of action is unclear.
• E2F transcription factors are key regulators of gene expression during cell proliferation and differentiation.

Purpose of the Study:

• To elucidate the mechanism of PAD4 action in inflammatory pathways.
• To investigate the role of E2F-1 citrullination in gene regulation and inflammatory responses.

Main Methods:

• Investigated PAD4-mediated citrullination of E2F-1 in inflammatory cells.
• Analyzed the effect of citrullination on E2F-1 chromatin association with cytokine genes.
• Examined the interplay between PAD4, BRD4, and E2F-1 on gene promoters.
• Utilized a murine collagen-induced arthritis model to assess therapeutic efficacy.

Main Results:

• PAD4 citrullinates E2F-1, promoting its association with cytokine gene promoters in granulocytes.
• Citrullination enhances BRD4 binding to acetylated E2F-1, forming a complex on cytokine gene promoters.
• Combined inhibition of PAD4 and BRD4 disrupts this complex, suppressing cytokine gene expression.
• Inhibition of PAD4 and BRD4 ameliorated disease progression in a collagen-induced arthritis model.

Conclusions:

• PAD4-mediated citrullination of E2F-1 is a novel mechanism driving inflammatory gene expression.
• The interplay between citrullination and acetylation of E2F-1 by PAD4 and BRD4 represents a regulatory interface for inflammation.
• Combined PAD4 and BRD4 inhibition shows therapeutic potential for inflammatory diseases.