Gene regulation via dynamic change of chromosomal conformation of remote enhancers

通过远程增强子染色体构象的动态变化进行基因调控

• 批准号: 21247002
• 负责人: SHIROISHI Toshihiko
• 金额: $ 28.62万
• 依托单位: National Institute of Genetics
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21247002/
• 关键词: 遺伝学・ゲノム・進化・動物・発生; 分化; 遺伝; ゲノム; 進化; 動物; 発生・分化; 遺伝子発現制御; 染色体ダイナミクス; 遠隔エンハンサー; 非翻訳保存配列; 形態形成; 進化発生学

Sonic hedgehog(Shh) encodes a signaling protein that plays pivotal roles in vertebrate development. Comparison of genomic sequences across mammalian species and teleost fishes revealed four conserved non-coding sequences(CNCSs) that cluster in a region 600 to 900 kb upstream of the Shh promoter. These CNCSs drive regional transgenic lacZ reporter expression in the limb bud and the epithelial lining of the oral cavity, pharynx and larynx(lung/gut), recapitulating the endogenous Shh expression. Targeted elimination of each of the four CNCSs from the mouse genome results in loss of endogenous Shh expression in specific regions, corresponding to the expression pattern of the transgenic LacZ reporter, and leads to regional-specific defect. The results indicate that these CNCSs are tissue-specific long-range Shh enhancers. The 3D-FISH and 3C analyses showed that the Shh promoter-enhancer occurs in a tissue specific manner. Thus, chromosome dynamics is a common mechanism to regulate the tissue-specific Shh expression by the long-range enhancers.

Sonic Hedgehog（Shh）编码一种信号蛋白，在脊椎动物发育中发挥关键作用。对哺乳动物物种和硬骨鱼基因组序列的比较揭示了四个保守的非编码序列（CNCS），它们聚集在Shh启动子上游600至900 kb的区域。这些 CNCS 驱动局部转基因 lacZ 报告基因在肢芽以及口腔、咽和喉（肺/肠）的上皮衬里表达，重现内源性 Shh 表达。从小鼠基因组中靶向消除四个 CNCS 中的每一个都会导致特定区域内源性 Shh 表达的丧失，这与转基因 LacZ 报告基因的表达模式相对应，并导致区域特异性缺陷。结果表明这些 CNCS 是组织特异性的长程 Shh 增强子。 3D-FISH 和 3C 分析表明，Shh 启动子增强子以组织特异性方式发生。因此，染色体动力学是长程增强子调节组织特异性Shh 表达的常见机制。

项目成果

Identification and characterization of new long conserved noncoding sequences in vertebrates

• DOI: 10.1007/s00335-008-9152-7
• 发表时间: 2008-12-01
• 期刊: MAMMALIAN GENOME
• 影响因子: 2.5
• 作者: Sakuraba, Yoshiyuki;Kimura, Toru;Gondo, Yoichi
• 通讯作者: Gondo, Yoichi

Long-range enhancer-promoter interaction via chromosomal dynamics at the Shh locus

通过 Shh 位点的染色体动力学实现长程增强子-启动子相互作用

• 发表时间: 2009
• 作者: 梶村好宏;船木一幸;篠原育;松本正晴;上野一磨;大塩裕哉;臼井英之;天野孝紀
• 通讯作者: 天野孝紀

Long-range enhancers directing regional Shh expression in the epithelial linings

长程增强子指导上皮内层局部 Shh 表达

• 发表时间: 2012
• 作者: Rana Syed Masud;Hitoshi Mimura;Yuji Sasaki and Masaki Ozawa;Shiroishi T.
• 通讯作者: Shiroishi T.

Chromosome dynamics underlying regulation of developmental Shh expression

发育 Shh 表达调控的染色体动力学

• 发表时间: 2009
• 作者: Amano T;Tanabe H;Sagai T. and Shiroishi T.
• 通讯作者: Sagai T. and Shiroishi T.

Long-range enhancers regulate developmental Shh expression via chromosomal dynamics

长程增强子通过染色体动力学调节发育Shh表达

• 发表时间: 2010
• 作者: 佐々木 祐二;須郷 由美;川崎 武志;鈴木 智也;池田 泰久;中瀬 正彦;竹下 健二;Shiroishi T.
• 通讯作者: Shiroishi T.