Human PAD4 regulates histone arginine methylation levels via demethylimination.
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.
Wang
Yanming
Y
Department of Genetic Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Wysocka
Joanna
J
Sayegh
Joyce
J
Lee
Young-Ho
YH
Perlin
Julie R
JR
Leonelli
Lauriebeth
L
Sonbuchner
Lakshmi S
LS
McDonald
Charles H
CH
Cook
Richard G
RG
Dou
Yali
Y
Roeder
Robert G
RG
Clarke
Steven
S
Stallcup
Michael R
MR
Allis
C David
CD
Coonrod
Scott A
SA
D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism*; D015153:Blotting, Western; D000001:Calcimycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002956:Citrulline / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics; D008744:Methylamines / Q000378:metabolism; D008745:Methylation; D008969:Molecular Sequence Data; D053766:Presenilin-2; D011401:Promoter Regions, Genetic; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
D006657:Histones; D007476:Ionophores; D008565:Membrane Proteins; D008744:Methylamines; C508861:PSEN2 protein, human; D053766:Presenilin-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D002956:Citrulline; D000001:Calcimycin; D001120:Arginine; C027451:methylamine; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases