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.

Download full-text


Available from: Young-Ho Lee, Oct 03, 2015
1 Follower
40 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    RNA 02/2015; 21(3):347-359. DOI:10.1261/rna.045138.114 · 4.94 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We developed a novel BLAST-Based Relative Distance (BBRD) method by Pearson’s correlation coefficient to avoid the problems of tedious multiple sequence alignment and complicated outgroup selection. We showed its application on reconstructing reliable phylogeny for nucleotide and protein sequences as exemplified by the fmr-1 gene and dihydrolipoamide dehydrogenase, respectively. We then used BBRD to resolve 124 protein arginine methyltransferases (PRMTs) that are homologues of nine mammalian PRMTs. The tree placed the uncharacterized PRMT9 with PRMT7 in the same clade, outside of all the Type I PRMTs including PRMT1 and its vertebrate paralogue PRMT8, PRMT3, PRMT6, PRMT2 and PRMT4. The PRMT7/9 branch then connects with the type II PRMT5. Some non-vertebrates contain different PRMTs without high sequence homology with the mammalian PRMTs. For example, in the case of Drosophila arginine methyltransferase (DART) and Trypanosoma brucei methyltransferases (TbPRMTs) in the analyses, the BBRD program grouped them with specific clades and thus suggested their evolutionary relationships. The BBRD method thus provided a great tool to construct a reliable tree for members of protein families through evolution.
    Molecular Phylogenetics and Evolution 01/2015; 84. DOI:10.1016/j.ympev.2014.12.002 · 3.92 Impact Factor
  • Source
    • "In contrast, a growing body of evidence links PADI enzymes to chromatin activities. Most likely, PADI4 catalyzes the citrullination of histone H4 at arginine 3 (Wang et al. 2004), while PADI2 (localized in the nucleus) appears to target histone H3 (Cherrington et al. 2010). A recent study suggests that histone citrullination may play an important role in facilitating gene expression in early embryos by creating a ''platform'' for HAT assembly leading to the enhancement of histone acetylation (Kan et al. 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The complexity of the genome is regulated by epigenetic mechanisms, which act on the level of DNA, histones, and nucleosomes. Epigenetic machinery is involved in various biological processes, including embryonic development, cell differentiation, neurogenesis, and adult cell renewal. In the last few years, it has become clear that the number of players identified in the regulation of chromatin structure and function is still increasing. In addition to well-known phenomena, including DNA methylation and histone modification, new, important elements, including nucleosome mobility, histone tail clipping, and regulatory ncRNA molecules, are being discovered. The present paper provides the current state of knowledge about the role of 16 different histone post-translational modifications, nucleosome positioning, and histone tail clipping in the structure and function of chromatin. We also emphasize the significance of cross-talk among chromatin marks and ncRNAs in epigenetic control.
    Neurotoxicity Research 12/2014; 27(2). DOI:10.1007/s12640-014-9508-6 · 3.54 Impact Factor
Show more