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Review
. 2024 Jun 22;12(4):101355.
doi: 10.1016/j.gendis.2024.101355. eCollection 2025 Jul.

Citrullination in health and disease: From physiological function to gene regulation

Affiliations
Review

Citrullination in health and disease: From physiological function to gene regulation

Xiaoya Zhang et al. Genes Dis. .

Abstract

Protein citrullination involves the deimination of arginine or methylarginine residues in peptide chains to form citrulline by peptidyl arginine deiminases. This process is an important protein post-translational modification that affects molecular structure and function of various proteins, including histones. In recent years, protein citrullination has attracted widespread attention for its influence on gene transcription. Studies on the impact of protein citrullination modification on chromatin structure remodeling and the establishment of gene regulatory networks have made rapid progress. In this review, we briefly summarize the physiological functions of protein citrullination modification. Specifically, we comprehensively outline the latest progress in the study of the role of protein citrullination modification in gene transcription regulation, focusing on the interaction of protein citrullination with other post-translational modifications.

Keywords: Citrullination; Deimination; Histone; Peptidyl arginine deiminase; Therapeutic interventions; Transcriptional control.

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Figures

Figure 1
Figure 1
The reaction mechanism of protein arginine citrullination is catalyzed by PAD.
Figure 2
Figure 2
Protein citrullination in physiological and pathological processes. Under physiological conditions, PAD is activated in specific cellular environments such as cell proliferation and differentiation, cellular stress and damage repair, hormonal regulation and immune modulation. Depending on its expression in different tissues, PAD regulates skin homeostasis and formation and participates in cell apoptosis, neuronal myelination development, the immune response and gene regulation. An imbalance in one of these activation signals or PAD dysfunction, can lead to abnormal levels of citrullination, which may contribute to the development of conditions such as cicatricial alopecia, dermatological disorders, multiple sclerosis, rheumatoid arthritis and cancer.
Figure 3
Figure 3
Chromatin opening through PAD-mediated citrullination of histone tails. Citrullination of histone tails removes positive charges, thus enhancing the repulsive force between histones and DNA. This PTM facilitates the access of DNA-binding proteins to DNA. The binding and recruitment of SWI/SNF complex remodeling factors promote the binding of sequence-specific factors, enabling more effective access of RNA Polymerase II and transcription factors to transcribe DNA into mRNA.
Figure 4
Figure 4
Crosstalk diagram between citrullination and other modifications. (A) PAD2 citrullination and PRC2 complex antagonism and crosstalk with LSD1 regulate ERα gene expression. SAM: S-adenosyl methionine (cofactor); PRC2: polycomb repressive complex 2 (methyltransferase activity); E2: 17-β-estradiol; LSD1: lysine-specific demethylase. (B) PAD4-mediated crosstalk between citrulline and acetylation. PAD4 promotes the recruitment of E2F-1 to cytokine target gene promoters, where E2F-1 interacts with BRD4 to drive inflammatory gene expression. (C) PAD4 and HDAC1/2 collaborate to regulate the expression of target genes. HDAC2 and PAD4 interact with p53 through distinct structural domains, leading to the downregulation of gene expression at p53 target gene promoters. Following DNA damage, PAD4 and HDAC2 dissociate from p53 target gene promoters, and recruitment of P300/CBP for acetylation results in transcriptional activation. (D) The PAD4-mediated c-Fos activation illustrates the crosstalk facilitated by the co-factor, Elk-1. On the c-Fos promoter, Elk-1 forms a complex with p300. Upon stimulation by EGF, the catalytic activity of PAD4 promotes the phosphorylation of Elk-1 by mitogen-activated protein kinase 1 (MAPK1). This phosphorylation event enhances the interaction between Elk-1 and p300, leading to acetylation of histone H4 and transcriptional activation of the c-Fos gene.

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References

    1. Taverna S.D., Li H., Ruthenburg A.J., Allis C.D., Patel D.J. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol. 2007;14(11):1025–1040. - PMC - PubMed
    1. Rothbart S.B., Strahl B.D. Interpreting the language of histone and DNA modifications. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 2014;1839(8):627–643. - PMC - PubMed
    1. Horibata S.C.S., Cherrington B.D. Role for peptidylarginine deiminase enzymes in disease and female reproduction. J Reprod Dev. 2012;58(3):274–282. - PubMed
    1. Arita K.H.H., Shimizu T., Nakashima K., Yamada M., Sato M. Structural basis for Ca(2+)-induced activation of human PAD4. Nat Struct Mol Biol. 2004;11(8):777–783. - PubMed
    1. Cosgrove M.S., Wolberger C. How does the histone code work? Biochem Cell Biol. 2005;83(4):468–476. - PubMed

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