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GENES & DEVELOPMENT 22:37-49, 2008
©2008 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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Deubiquitylation of histone H2A activates transcriptional initiation via trans-histone cross-talk with H3K4 di- and trimethylation

Takeya Nakagawa1, Takuya Kajitani1, Shinji Togo2, Norio Masuko3, Hideki Ohdan4, Yoshitaka Hishikawa1, Takehiko Koji1, Toshifumi Matsuyama1, Tsuyoshi Ikura5, Masami Muramatsu6, and Takashi Ito1,7

1 Nagasaki University School of Medicine, Nagasaki 852-8523, Japan; 2 Department of Surgery II, Yokohama City University School of Medicine, Yokohama 236-0004, Japan; 3 Hanno Research Center, Taiho Pharmaceutical Co. Ltd., Saitama, 357-8527 Japan; 4 Department of Surgery, Hiroshima University School of Medicine, Hiroshima, 734-8553 Japan; 5 Department of Biochemistry, Tohoku University School of Medicine, Sendai 980-8575 Japan; 6 Saitama Medical School Research Center for Genomic Medicine, Saitama 350-1241, Japan

Transcriptional initiation is a key step in the control of mRNA synthesis and is intimately related to chromatin structure and histone modification. Here, we show that the ubiquitylation of H2A (ubH2A) correlates with silent chromatin and regulates transcriptional initiation. The levels of ubH2A vary during hepatocyte regeneration, and based on microarray expression data from regenerating liver, we identified USP21, a ubiquitin-specific protease that catalyzes the hydrolysis of ubH2A. When chromatin is assembled in vitro, ubH2A, but not H2A, specifically represses the di- and trimethylation of H3K4. USP21 relieves this ubH2A-specific repression. In addition, in vitro transcription analysis revealed that ubH2A represses transcriptional initiation, but not transcriptional elongation, by inhibiting H3K4 methylation. Notably, ubH2A-mediated repression was not observed when H3 Lys 4 was changed to arginine. Furthermore, overexpression of USP21 in the liver up-regulates a gene that is normally down-regulated during hepatocyte regeneration. Our studies revealed a novel mode of trans-histone cross-talk, in which H2A ubiquitylation controls the di- and trimethylation of H3K4, resulting in regulation of transcriptional initiation.

[Keywords: Nucleosome; ubiquitylation; histone code; transcription; USP21; H2A]]

Received August 27, 2007; revised version accepted November 1, 2007.

7 Corresponding author.

E-MAIL tito{at}net.nagasaki-u.ac.jp; FAX 81-95-819-7040.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1609708


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