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Originally published in Science Express on 2 September 2004
Science 8 October 2004:
Vol. 306. no. 5694, pp. 279 - 283
DOI: 10.1126/science.1101400
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Human PAD4 Regulates Histone Arginine Methylation Levels via Demethylimination

Yanming Wang,1,2 Joanna Wysocka,1,2 Joyce Sayegh,3 Young-Ho Lee,4 Julie R. Perlin,1 Lauriebeth Leonelli,1 Lakshmi S. Sonbuchner,1 Charles H. McDonald,5 Richard G. Cook,5 Yali Dou,6 Robert G. Roeder,6 Steven Clarke,3 Michael R. Stallcup,4 C. David Allis,2* Scott A. Coonrod1*

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.

1 Department of Genetic Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
2 Laboratory of Chromatin Biology, Rockefeller University, Box 78, 1230 York Avenue, New York, NY 10021, USA.
3 Department of Chemistry and Biochemistry and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA 90095–1569, USA.
4 Department of Pathology, University of Southern California, Los Angeles, CA 90089–9092, USA.
5 Department of Microbiology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
6 Laboratory of Biochemistry and Molecular Biology, Rockefeller University, New York, NY 10021, USA.

* To whom correspondence should be addressed. E-mail: alliscd{at}rockefeller.edu (C.D.A.); scc2003{at}med.cornell.edu (S.A.C.)

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