Histone Deimination Antagonizes Arginine Methylation

Abstract

Methylation of arginine residues within histone H3 has been linked to active transcription. This modification appears on the estrogen-regulated pS2 promoter when the CARM1 methyltransferase is recruited during transcriptional activation. Here we describe a process, deimination, that converts histone arginine to citrulline and antagonizes arginine methylation. We show that peptidyl arginine deiminase 4 (PADI4) specifically deiminates, arginine residues R2, R8, R17, and R26 in the H3 tail. Deimination by PADI4 prevents arginine methylation by CARM1. Dimethylation of arginines prevents deimination by PADI4 although monomethylation still allows deimination to take place. In vivo targeting experiments on an endogenous promoter demonstrate that PADI4 can repress hormone receptor-mediated gene induction. Consistent with a repressive role for PADI4, this enzyme is recruited to the pS2 promoter following hormone induction when the gene is transcriptionally downregulated. The recruitment of PADI4 coincides with deimination of the histone H3 N-terminal tail. These results define deimination as a novel mechanism for antagonizing the transcriptional induction mediated by arginine methylation.

Regulation of histone modification and chromatin structure by the p53–PADI4 pathway

“…2c). Although PADI4 was reported to function as demethylase of mono-methyl-H4R3 in vitro 19,20 , PADI4 activation did not affect H4R3 methylation status in our experimental system (Supplementary Fig. S1).…”

Inhibitors and Inactivators of Protein Arginine Deiminase 4: Functional and Structural Characterization,

“…For example, PAD4 deiminates multiple transcriptional regulators, including p300, a histone acetyltransferase (HAT) (23) that acts as a transcriptional coactivator, and histones H2A, H3, and H4 (24,25). Interestingly, the deimination of p300 and the histone proteins appears to have opposite effects on transcriptional regulation; i.e., the modification of p300 enhances its ability to activate the expression of an artificial reporter construct (23), whereas the deimination of histones H3 and H4 represses the expression of genes under the control of the estrogen receptor (20,21).…”

La désimination ou citrullination

“…En 2004, deux équipes indépendantes démontraient sa capacité à modifier en citrullines les arginines mono-méthylées des histones [29,30]. En coordination avec d'autres modifications post-traductionnelles comme la méthylation des arginines des histones nucléosomales, la désimination joue donc aussi un rôle dans l'information épigénétique, participant à la plasticité du code « histone » (pour revue voir [31]) et donc au contrôle de l'expression génique.…”