Human PAD4 Regulates Histone Arginine Methylation Levels via Demethylimination

Cornell University, Итак, New York, United States
Science (Impact Factor: 33.61). 11/2004; 306(5694):279-83. DOI: 10.1126/science.1101400
Source: PubMed


Methylation of arginine (Arg) and lysine residues in histones has been correlated with epigenetic forms of gene regulation.
Although histone methyltransferases are known, enzymes that demethylate histones have not been identified. Here, we demonstrate
that human peptidylarginine deiminase 4 (PAD4) regulates histone Arg methylation by converting methyl-Arg to citrulline and
releasing methylamine. PAD4 targets multiple sites in histones H3 and H4, including those sites methylated by coactivators
CARM1 (H3 Arg17) and PRMT1 (H4 Arg3). A decrease of histone Arg methylation, with a concomitant increase of citrullination, requires PAD4 activity in human HL-60
granulocytes. Moreover, PAD4 activity is linked with the transcriptional regulation of estrogen-responsive genes in MCF-7
cells. These data suggest that PAD4 mediates gene expression by regulating Arg methylation and citrullination in histones.

    • "ETosis is characteristically associated with chromatin decondensation that is regulated by peptidyl arginine deiminase 4 (PAD4)-mediated histone hypercitrullination (Rohrbach and others 2012). PAD4, a Ca 2+ -dependent enzyme , converts the arginine side chains of histones to citrulline by deimination (Wang and others 2004). The inhibition of PAD4 activity by Cl-amidine or neutrophils isolated from PAD4-deficient mice is unable to induce histone citrullination, chromatin decondensation, and extracellular traps (Wang and others 2009; Li and others 2010). "
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    ABSTRACT: Treatment of interferon-γ (IFN-γ) causes cell growth inhibition and cytotoxicity in lung epithelial malignancies. Regarding the induction of autophagy related to IFN-γ signaling, this study investigated the link between autophagy and IFN-γ cytotoxicity. In A549 human lung cancer cells, IFN-γ treatment induced concurrent apoptotic and nonapoptotic events. Unexpectedly, the nonapoptotic cells present mimic extracellular trap cell death (ETosis), which was regulated by caspase-3 and by autophagy induction through immunity-related GTPase family M protein 1 and activating transcription factor 6. Furthermore, IFN-γ signaling controlled mimic ETosis through a mechanism involving an autophagy- and Fas-associated protein with death domain-controlled caspase-8/-3 activation. Following caspase-mediated lamin degradation, IFN-γ caused DNA damage-associated ataxia telangiectasia and Rad3-related protein (ATR)/ataxia telangiectasia mutated (ATM)-regulated mimic ETosis. Upon ATR/ATM signaling, peptidyl arginine deiminase 4 (PAD4)-mediated histone 3 citrullination promoted mimic ETosis. Such IFN-γ-induced effects were defective in PC14PE6/AS2 human lung cancer cells, which were unsusceptible to IFN-γ-induced autophagy. Due to autophagy-based caspase cascade activation, IFN-γ triggers unconventional caspase-mediated DNA damage, followed by ATR/ATM-regulated PAD4-mediated histone citrullination during mimic ETosis in lung epithelial malignancy.
    No preview · Article · Nov 2015 · Journal of Interferon & Cytokine Research
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    • "Arginine methylation is catalyzed by protein arginine methyltransferases , a family of enzymes composed by 11 members (protein arginine methyltransferases 1–11) in mammalian cells (Bedford and Clarke, 2009). Although no arginine demethylase has been identified, a well-studied modification of arginine residues that precludes methylation is deamination, which is catalyzed by peptidylarginine deiminases, enzymes that convert methylated arginine into citrulline (Cuthbert et al., 2004; Migliori et al., 2010; Wang et al., 2004). This vast and expanding literature reveals the level of complexity of epigenetic regulation, which includes the action of multiple enzymes and post-translational modifications on specific histone residues, thereby defining complex histone code modulating the transcriptional output at particular gene loci (Table 1). "
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    ABSTRACT: The recent years have been characterized by a surge of studies on the role of transcription factors and histone modifications in regulating the progression of progenitors into oligodendrocytes. This review summarizes this body of evidence and presents an integrated view of transcriptional networks and epigenetic regulators defining proliferating progenitors and their differentiation along the oligodendrocyte lineage. We suggest that transcription factors in proliferating progenitors have direct access to DNA, due to predominantly euchromatic nuclei. As progenitors differentiate, however, transcriptional competence is modulated by the formation of heterochromatin, which modifies the association of DNA with nucleosomal histones and renders the access of transcription factors dependent on the activity of epigenetic modulators. These concepts are delineated within the context of development, and the potential functional implications are discussed. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Preview · Article · Mar 2015 · Glia
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    • "Currently, the best understood biological role for this antagonism is in the regulation of chromatin structure. For example , PADI4 catalyzed deimination of histone H3 at Arg17 and histone H4 at Arg 3 has been linked to transcriptional repression (Cuthbert et al. 2004; Wang et al. 2004). Conversely, citrullination of histone H3R26 by PADI2 has been shown to facilitate transcriptional activation at target genes (Zhang et al. 2012). "
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    ABSTRACT: Splicing factor proline- and glutamine-rich (SFPQ) also commonly known as polypyrimidine tract-binding protein-associated-splicing factor (PSF) and its binding partner non-POU domain-containing octamer-binding protein (NONO/p54nrb), are highly abundant, multifunctional nuclear proteins. However, the exact role of this complex is yet to be determined. Following purification of the endogeneous SFPQ/NONO complex, mass spectrometry analysis identified a wide range of interacting proteins, including those involved in RNA processing, RNA splicing, and transcriptional regulation, consistent with a multifunctional role for SFPQ/NONO. In addition, we have identified several sites of arginine methylation in SFPQ/PSF using mass spectrometry and found that several arginines in the N-terminal domain of SFPQ/PSF are asymmetrically dimethylated. Furthermore, we find that the protein arginine N-methyltransferase, PRMT1, catalyzes this methylation in vitro and that this is antagonized by citrullination of SFPQ. Arginine methylation and citrullination of SFPQ/PSF does not affect complex formation with NONO. However, arginine methylation was shown to increase the association with mRNA in mRNP complexes in mammalian cells. Finally we show that the biochemical properties of the endogenous complex from cell lysates are significantly influenced by the ionic strength during purification. At low ionic strength, the SFPQ/NONO complex forms large heterogeneous protein assemblies or aggregates, preventing the purification of the SFPQ/NONO complex. The ability of the SFPQ/NONO complex to form varying protein assemblies, in conjunction with the effect of post-translational modifications of SFPQ modulating mRNA binding, suggests key roles affecting mRNP dynamics within the cell.
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