Editors' ChoiceHISTONES

Regulating Transcription Through Arginine Deimination

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Science's STKE  14 Sep 2004:
Vol. 2004, Issue 250, pp. tw321
DOI: 10.1126/stke.2502004tw321

Posttranslational modifications of histones, the proteins around which DNA is wound, help regulate chromatin structure and function. For instance, transcriptional activation by estrogen is associated with arginine methylation of histone H3. Although cycles of arginine methylation have been observed during the activation of estrogen-responsive genes, the mechanisms whereby methylation is lost remain unclear. Cuthbert et al. used a combination of Western analysis; truncated H3, N-terminal sequencing; and mass spectrometry to show that PADI4 (peptidyl arginine deiminase 4) catalyzed the in vitro conversion of arginines Arg2, Arg8, Arg17, and Arg26 in the H3 tail to citrulline. Overexpression of PADI4 in MCF-7 cells indicated that H3 tail arginines were also deiminated in vivo. Arginine deimination blocked H3 methylation by the methyltransferase CARM1 and, although PADI4 could not deiminate dimethylated arginines, it appeared to deiminate monomethyl arginine. When PADI4 and either the estrogen receptor ligand binding domain or the thyroid hormone ligand binding domain were recruited to the VEGF-A promoter by means of fusion proteins that targeted nearby DNA binding domains, PADI4 inhibited hormone-dependent transcriptional activation of VEGF-A. Estrogen produced an increase in the PADI4 content of MCF-7 cells, and chromatin immunoprecipitation (ChIP) analysis indicated that it stimulated PADI4 recruitment to the pS2 promoter in parallel with arginine deimination to citrulline and a loss of RNA polymerase II from the promoter. Thus, the authors propose that PADI4 deimination of arginine represents a novel hormone-sensitive mechanism for antagonizing arginine methylation and the ensuing transcriptional activation.

G. L. Cuthbert, S. Daujat, A. W. Snowden, H. Erdjument-Bromage, T. Hagiwara, M. Yamada, R. Schneider, P. D. Gregory, P. Tempst, A. J. Bannister, T. Kouzarides, Histone deimination antagonizes arginine methylation. Cell 118, 545-553 (2004). [Online Journal]

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