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.

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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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    • "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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    • "Compared with other posttranslational modification systems, the writers (PRMTs) of protein arginine methylation are best studied. Putative demethylase erasers such as peptidylarginine deiminases (PADIs) that may convert MMA residues into citrullines (Cuthbert et al., 2004; Wang et al., 2004) or JMJD6 that is likely to remove one methyl group from DMAs (Chang et al., 2007) have been reported. However , there were few follow-up studies and the reaction catalyzed by PADI4, the only PADI that can convert MMA, is deimination but not demethylation. "
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