Phosphorylation and ubiquitylation of H2A regulate chromatin structure and function

H2A 的磷酸化和泛素化调节染色质结构和功能

• 批准号: 17390083
• 负责人: ITO Takashi
• 金额: $ 9.22万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390083/
• 关键词: histone; acetylation; phosphorylation; nucleosome; chromatin; transcription; 再構築; エピジェネティクス; 翻訳後修飾

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.

基因组DNA以核蛋白复合体的形式存在，称为染色质。这项工作是基于这样一个假设，即染色质动力学和结构是DNA依赖过程分析的一个组成部分。翻译后的组蛋白修饰对于许多生物现象的调节是重要的。转录启动是控制mRNA合成的关键步骤，与染色质结构和组蛋白修饰密切相关。然而，人们对组蛋白修饰如何影响转录启动知之甚少。在这里，我们证明了H_2A的泛素化(UbH_2A)与沉默的染色质相关，并调节转录的启动。UbH2A在肝细胞再生过程中的水平不同，基于再生肝脏的微阵列表达数据，我们已经确定USP21是一个潜在的调节因子。我们发现，USP21是一种泛素专一性的蛋白酶，在体外可以催化ubUSP21的水解。当染色质在体外组装时，ubH2A，而不是H2A，特异性地抑制了H3K4的甲基化。USP21解除了这种ubH2A特异的抑制作用。H3赖氨酸4的甲基化似乎是ubH2A抑制的目标，因为H3赖氨酸4到精氨酸的突变不能被抑制。此外，在体内，将USP21电穿孔到肝脏中可以上调Serpina6，这是一个在肝细胞再生过程中通常下调的基因。在这个项目中，我们阐明了一种新的反式组蛋白串扰模式，在这种模式中，H_2A泛素化控制H3K4的甲基化，从而调节转录启动。

项目成果

Linker histone variants control chromatin dynamics during early embryogenesis

• DOI: 10.1073/pnas.0409824102
• 发表时间: 2005-04-19
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Saeki, H;Ohsumi, K;Kaneda, Y
• 通讯作者: Kaneda, Y

クロマチン再構築因子

染色质重塑因子

• 发表时间: 2006
• 期刊: 蛋白質核酸酵素 51
• 作者: 難波泰明;梶谷卓也;中川武弥;伊藤 敬
• 通讯作者: 伊藤 敬

Crystallization and preliminary X-ray characterization of aminopeptidase N from Escherichia coli

• DOI: 10.1107/s1744309106021567
• 发表时间: 2006-07-01
• 期刊: ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
• 影响因子: 0.9
• 作者: Onohara, Yuko;Nakajima, Yoshitaka;Yoshimoto, Tadashi
• 通讯作者: Yoshimoto, Tadashi

A histone code in meiosis:: the histone kinase, NHK-1, is required for proper chromosomal architecture in Drosophila oocytes

• DOI: 10.1101/gad.1348905
• 发表时间: 2005-11-01
• 期刊: GENES & DEVELOPMENT
• 影响因子: 10.5
• 作者: Ivanovska, I;Khandan, T;Orr-Weaver, TL
• 通讯作者: Orr-Weaver, TL

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)

转录研究强化硕士（第 3 章染色质重塑第 62-72 页）

• 发表时间: 2005
• 作者: 半田宏ら編集;伊藤敬ら分担
• 通讯作者: 伊藤敬ら分担