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Structure and function of a imprinting center in the region of human SNRPN gene

人类SNRPN基因印记中心的结构和功能

基本信息

批准号：
09672312
负责人：
NAKAO Mitsuyoshi
金额：
$ 1.92万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672312/
关键词：
genomic imprinting DNA methylation methyl-CpG binding protein CpG island imprinting center enhancer competition direct repeat transcriptional factor DNA複製 CpGアイランドプラダー・ビリ-症候群 SNRPN GABAレセプター

项目摘要

Certain mammalian genes are expressed exclusively from either the paternal and the maternal chromosome because of a differential marking process that occurs during gametogenesis. This epigenetic marking is called genomic imprinting. I focused on an imprinted SNRPN gene region in the Prader-Willi/Angelman syndrome. Our data revealed the correlations between the differential SNRPN gene activity and the changes in DNA methylation, higher order chromatin structure and replication timing. Further, we isolated and characterized a new member of the methyl-CpG binding proteins, named PCM1 (MBD1), which possesses a methyl-CpG binding domain and cysteine-rich CXXC regions. Four PCM1 isoforms were newly identified to be alternatively spliced in the CXXC domains and the C-terminus. All forms of PCM1 inhibited the promoter activity of SNRPN gene via methylation. Interestingly, three copies of the CXXC domain in the PCM1 isoforms enhanced the suppressive effect on the transcription from both methylated and unmethylated SNRPN promoters. In contrast, PCM1 isoforms containing two copies of the CXXC domain inhibited methylated but not unmethylated promoter, suggesting that the CXXC domain is a regulatory element of PCMI.These findings suggested that methyl-CpG binding proteins play important roles in methylation-mediated transcriptional silencing of SNRPN gene.

由于配子体发生过程中的差异标记过程，某些哺乳动物的基因只在父系和母系染色体上表达。这种表观遗传标记被称为基因组印记。我专注于Prader-Willi/Angelman综合征的一个印迹SNRPN基因区域。我们的数据揭示了SNRPN基因活性差异与DNA甲基化、高阶染色质结构和复制时间的变化之间的相关性。此外，我们分离并鉴定了甲基- cpg结合蛋白的新成员PCM1 (MBD1)，该成员具有甲基- cpg结合结构域和富含半胱氨酸的CXXC区域。四个PCM1同工异构体被新鉴定为在CXXC结构域和c端选择性剪接。所有形式的PCM1通过甲基化抑制SNRPN基因的启动子活性。有趣的是，PCM1亚型中CXXC结构域的三个拷贝增强了对甲基化和非甲基化SNRPN启动子转录的抑制作用。相比之下，含有两个拷贝CXXC结构域的PCM1亚型抑制甲基化启动子，但不抑制未甲基化启动子，这表明CXXC结构域是PCMI的一个调控元件。这些发现表明甲基化cpg结合蛋白在SNRPN基因甲基化介导的转录沉默中起重要作用。