Phosphorylation and ubiquitylation of H2A regulate chromatin structure and function

• Project/Area Number: 17390083
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Nagasaki University
• Principal Investigator: ITO Takashi Nagasaki University, Graduate School of Biomedical Sciences, Professor, 大学院医歯薬学総合研究科, 教授 (90306275)
• Co-Investigator(Kenkyū-buntansha): YASUI Kyoshi Nagasaki University, Graduate School of Biomedical Sciences, Research Associate, 大学院医歯薬学総合研究科, 助手 (50372777) ; NAKAGAWA Takeya Nagasaki University, Graduate School of Biomedical Sciences, Research Associate, 大学院医歯薬学総合研究科, 助手 (50363502) ; 沖 昌也 長崎大学, 大学院医歯薬学総合研究科, 助手 (60420626)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥14,400,000 (Direct Cost: ¥14,400,000); Fiscal Year 2006: ¥6,800,000 (Direct Cost: ¥6,800,000); Fiscal Year 2005: ¥7,600,000 (Direct Cost: ¥7,600,000)
• Keywords: histone / acetylation / phosphorylation / nucleosome / chromatin / transcription / 再構築 / エピジェネティクス / 翻訳後修飾

Research Abstract

GenomicDNA exists as a nucleoprotein complex termed chromatin. The work is based on the hypothesis that chromatin dynamics and structure are an integral component of the analysis of DNA-dependent processes. Posttranslational histone modifications are important for the regulation of many biological phenomena. Transcriptional initiation is a key step in the control of mRNA synthesis and is essentially related to chromatin structure and histone modification. However, very little is known how histone modification affects transcriptional initiation. Here, we show that the ubiquitylation of H2A (ubH2A) correlates with silent chromatin and regulates transcriptional initiation. Levels of ubH2A vary during hepatocyte regeneration, and based on microarray expression data from regenerating liver, we have identified USP21 as a potential regulator. We have found that USP21, a ubiquitin-specific protease, catalyzes the hydrolysis of ubUSP21 in vitro. When chromatin is assembled in vitro, ubH2A, but not H2A, specifically repressed the methylation of H3K4. USP21 relieved this ubH2A-specific repression. Methylation of H3 lysine 4 appears to be the target of the ubH2A repression, as a H3 lysine 4 to arginine mutant cannot be repressed. Furthermore, in vivo electroporation of USP21 into the liver up-regulated Serpina6, a gene that is normally down-regulated during hepatocyte regeneration. In this project we clarified a novel mode of trans-histone crosstalk, in which H2A ubiquitylation controls the methylation of H3K4 resulting in regulation of transcriptional initiation.

Research Products

• [Journal Article] Regulation of histone acetylation and nucleosome assembly by transcription factor JDP2. (2006)
  • Author(s): Jin, C., K.Kato, T.Chimura, T.Yamasaki, K.Nakade, T.Murata, H.Li, J.Pan, M.Zhao, K.Sun, R.Chiu, T.Ito et al.
  • Journal Title: Nature Structural ＆ Molecular Biology. Published online : 5 March 2006
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of histone acetylation and nucleosome assembly by transcription factor JDP2. (2006)
  • Author(s): Jin, C., Kato, K., Chimura, T., Yamasaki, T., Nakade, K., Murata, T., Li, H., Pan, J., Zhao, M., Sun, K., Chiu, R., Ito, T., Nagata, K., Horikoshi, M., Yokoyama, K.K.
  • Journal Title: Nat Struct Mol Biol 13(4) Pages: 331-338
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli : Crystal structure and conformational change of the methionine 260 residue involved in substrate recognition. (2006)
  • Author(s): Ito, K., Nakajima, Y., Onohara, Y., Takeo, M., Nakashima, K., Matsubara, F., Ito, T., Yoshimoto, T.
  • Journal Title: J Biol Chem 281(44) Pages: 33664-33676
• [Journal Article] Regulation of histone acetylation and nucleosome assembly by transcription factor JDP2. (2006)
  • Author(s): Jin, C., Kato, K., Chimura, T., Yamasaki, T., Nakade, K., Murata, T., Li, H., Pan, J., Zhao, M., Sun, K., Chiu, R., Ito, T., Nagata, K., Horikoshi, M., Yokoyama, K.K.
  • Journal Title: Nat Struct Mol Biol 13(4): Pages: 331-338
• [Journal Article] Crystal structure and mechanism of tripeptidyl activity of prolyl tripeptidyl aminopeptidase from Porphyromonas gingivalis. (2006)
  • Author(s): Ito, K., Nakajima, Y., Xu, Y., Yamada, N., Onohara, Y., Ito, T., Matsubara, F., Kabashima, T., Nakayama, K., Yoshimoto, T.
  • Journal Title: J Mol Biol 362(2) Pages: 228-240
• [Journal Article] Crystallization and preliminary x-ray characterization of aminopeptidase N from Escherichia coli. (2006)
  • Author(s): Onohara, Y., Nakajima, Y., Ito, K., Xu, Y., Nakashima, K., Ito, T., Yoshimoto, T.
  • Journal Title: Acta Crystallograph Sect F Struct Biol Cryst Commun 62 Pages: 699-701
• [Journal Article] クロマチン再構築因子 (2006)
  • Author(s): 難波泰明, 梶谷卓也, 中川武弥, 伊藤 敬
  • Journal Title: 蛋白質核酸酵素 51 Pages: 2076-2082
• [Journal Article] クロマチン再構築因子 (2006)
  • Author(s): 梶谷卓也, 三笠昌樹, 伊藤 敬
  • Journal Title: 実験医学 24 Pages: 1069-1074
• [Journal Article] Regulation of histone acetylation and nucleosome assembly by transcription factor JDP2. (2006)
  • Author(s): Jin, C., K.Kato, T.Chimura, T.Yamasaki, K.Nakade, T.Murata, H.Li, J.Pan, M.Zhao, K.Sun, R.Chiu, T.Ito et al.
  • Journal Title: Nature Structural & Molecular Biology. (Published online : 5 March 2006)
• [Journal Article] The conserved kinase NHK-1 is essential for mitotic progression and unifying acentrosomal meiotic spindles in Drosophila melanogaster. (2005)
  • Author(s): Cullen, C.F., A.L.Brittle, T.Ito, H.Ohkura.
  • Journal Title: J Cell Biol 171 Pages: 593-602
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sox9 and p300 Cooperatively Regulate Chromatin-mediated Transcription. (2005)
  • Author(s): Furumatsu, T., M.Tsuda, K.Yoshida, N.Taniguchi, T.Ito, M.Hashimoto, H.Asahara
  • Journal Title: J Biol Chem 280 Pages: 35203-35208
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A histone code in meiosis : the histone kinase, NHK-1, is required for proper chromosomal architecture in Drosophila oocytes. (2005)
  • Author(s): Ivanovska, I., T.Khandan, T.Ito, T.L.Orr-Weaver.
  • Journal Title: Genes Dev 19 Pages: 2571-2582
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Linker histone variants control chromatin dynamics during early embryogenesis. (2005)
  • Author(s): Saeki, H., K.Ohsumi, H.Aihara, T.Ito, S.Hirose, K.Ura, Y.Kaneda.
  • Journal Title: Proc Natl Acad Sci USA 102 Pages: 5697-5702
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] クロマチンと病態 (2005)
  • Author(s): 中川 武弥, 田頭英樹, 沖昌也, 伊藤 敬
  • Journal Title: Molecular Medicine 42 Pages: 966-972
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sox9 and p300 Cooperatively Regulate Chromatin-mediated Transcription. (2005)
  • Author(s): Furumatsu, T., M.Tsuda, K.Yoshida, N.Taniguchi, T.Ito, M.Hashimoto, H.Asahara.
  • Journal Title: J Biol Chem 280 Pages: 35203-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Linker histone variants control chromatin dynamics during early embryogenesis. (2005)
  • Author(s): Saeki, H., K.Ohsumi, H.Aihara, T.Ito, S.Hirose, K.Ura, Y.Kaneda.
  • Journal Title: Proc Natl Acad Sci U S A 102 Pages: 5697-702
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] ク ロマチンと病態 (2005)
  • Author(s): 中川 武弥, 田頭英樹, 沖昌也, 伊藤 敬
  • Journal Title: Molecular Medicine 42 Pages: 966-972
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] クロマチンと病態 (2005)
  • Author(s): 中川 武弥, 田頭 英樹, 沖 昌也, 伊藤 敬
  • Journal Title: Molecular Medicine 42 Pages: 966-972
• [Book] 転写研究集中マスター(第3章クロマチンリモデリングp.62-72) (2005)
  • Author(s): 半田宏ら編集, 伊藤敬ら分担
  • Total Pages: 172
  • Publisher: 羊土社
  • Description: 「研究成果報告書概要(和文)」より