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Molecular mechanisms of gene-specific transcriptional regulation by histone methyl transferase

组蛋白甲基转移酶基因特异性转录调控的分子机制

基本信息

批准号：
14572142
负责人：
YAMAMOTO Ken
金额：
$ 1.86万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

Heterochromatin is the fraction of genome that remains condensed throughout the cell cycle, replicates in the late S phase, and is generally associated with pericentric and telomeric regions of chromosomes. Euchromatic genes placed into proximity of heterochromatin by chromosomal rearrangement or trans-recruitment will be variably, silenced, a phenomenon known as position effect variegation (PEV). The Polycomb group protein (PcG)-mediated gene silencing has often been compared with the heterochromatin-mediated one because some conserved domains observed in PcG proteins are shared with HP1 (chromodomain) and Su(var)3-9 (chromodomain and SET domain), and also because PcG proteins, like modifiers of PEV, are dosage sensitive.In order to elucidate molecular mechanisms of heterochromatin initiation and/or maintenance by SUV39H1-HP1 and SU(Z)12-EZH2 systems, we investigated interactions of these proteins. We found that 1) self-interaction through the chromo shadow domain of HP1 is crucial for recruitment of SUV39H1 onto nucleosomes 2) PcG SU(Z)12 directly interacts with HP1 and EZH2 and represses transcription in the presence of HP1. We suggest that a role for SU(Z)12 in the maintenance of heterochromatin and/or HP1-mediated transcriptional repression of euchromatic genes by recruiting EZH2 or EED-EZH2 complex onto HP1□-bound nucleosomes.

异染色质是基因组中在整个细胞周期中保持凝聚的部分，在S期后期进行复制，通常与染色体的中心周围区和端粒区有关。通过染色体重排或反式招募放置在异染色质附近的常染色质基因将不同程度地沉默，这种现象被称为位置效应变异（PEV）。Polycomb group protein （PcG）介导的基因沉默经常被与异染色质介导的基因沉默进行比较，因为在PcG蛋白中观察到的一些保守结构域与HP1（色域）和Su(var)3-9（色域和SET域）共享，也因为PcG蛋白与PEV修饰剂一样对剂量敏感。为了阐明SUV39H1-HP1和SU(Z)12-EZH2系统启动和/或维持异染色质的分子机制，我们研究了这些蛋白的相互作用。我们发现1)通过HP1的色影结构域的自相互作用对于SUV39H1在核小体上募集至关重要2)PcG SU(Z)12直接与HP1和EZH2相互作用，并在HP1存在时抑制转录。我们认为，SU(Z)12通过将EZH2或EED-EZH2复合物募集到HP1□结合的核小体上，在维持异染色质和/或HP1介导的常染色质基因的转录抑制中发挥作用。