权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Medical genetic research on molecular basis of epigenetic regulation and human diseases

表观遗传调控分子基础与人类疾病的医学遗传学研究

基本信息

批准号：
16209011
负责人：
NAKAO Mitsuyoshi
金额：
$ 31.62万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

The project focused on the investigations of epigenetic gene regulation and related genetic phenomena including human diseases, and discovered a lot of new findings on DNA methyltransferases (DNMT), methylated DNA binding proteins (MBD proteins), chromatin insulator, genomic imprinting, and differentiation of mouse germ cells and embryonic stem cells (ES cells). Dr. Sasaki's group developed germ cell-specific knockout mice for DNMT3A and DNMT3B, and reported that these mice were sterile, and that DNMT3A-mediated DNA methylation during gametogenesis is required for establishing genomic imprinting. This result had a great impact on the imprinting mechanisms. In addition, studies of mutant mice deficient for DNMT3A or its associated factor named DNMT3L showed that aberrations of meiosis and transcriptional repression of transposons occurred in their testis, and that embryos derived from eggs of these mutant mice had abnormal placenta, resulting in the miscarriage. Further, Sasaki's group … More studied the distribution of CpG dinucleotides in male or female germ cell-specific methylated regions, and showed that DNMT3L or related factors can be implicated in development of ICF syndrome.MBD1 functions as a DNA methylation-mediated transcriptional repressor. Nakao's group reported that MBD1 recruits histone methyltransferase SETDB1 and its activating factor MCAF1 (MBD1-containing chromatin associated factor), resulting ir transcriptional repression and heterochromatin formation that is marked with trimethylation of 9th lysine of histone H3. In this case, SUMOylation of MBD1 is important for forming the MBD1-MCAF1-SETDB1 repressive complexes. It was also found that MBD1 and polycomb group proteins have overlapping roles in transcriptional repression and heterochromatin formation. In addition, MBD domain of MeCP2, another type of MBD proteins, is frequently mutated in Rett syndrome, and most MBD mutants lost the ability to bind methylated DNAs. Nakao group found that some MBD mutants retained the methylated DNA binding, suggesting the presence of unidentified mechanisms to develop this disease. Further, in the boundary elements of human genome, insulator binding protein CTCF was found to cooperate with chromatin remodeling factor CHD8, resulting in the enhancer blocking effect on H191IGF2 imprinted region. This is a first evidence for insulator linked to epigenetic remodeling. In neural differentiation of mouse ES cells, PML bodies and chromocenters were found to be remarkably reorganized, and Oct3/4 gene locus was differentially marked with histone acetylation and methylation, and DNA methylation at each stage of ES cells, neural precursor cells and terminally differentiated neurons. Less

该项目侧重于表观遗传基因调控和相关遗传现象的研究，包括人类疾病，并在小鼠生殖细胞和胚胎干细胞(ES细胞)的DNA甲基转移酶(DNMT)、甲基化DNA结合蛋白(MBD蛋白)、染色质绝缘体、基因组印迹和分化方面发现了许多新发现。佐佐木博士的团队开发了针对DNMT3A和DNMT3B的生殖细胞特异性基因敲除小鼠，并报告称，这些小鼠是不育的，配子发生期间DNMT3A介导的DNA甲基化是建立基因组印记所必需的。这一结果对印迹机理产生了很大的影响。此外，对缺乏DNMT3A或其相关因子DNMT3L的突变小鼠的研究表明，这些突变小鼠的睾丸发生了减数分裂和转座子转录抑制的异常，这些突变小鼠来自鸡蛋的胚胎有异常的胎盘，导致流产。此外，佐佐木的组合…进一步研究了CpG二核苷酸在男性或女性生殖细胞特异性甲基化区域的分布，发现DNMT3L或相关因素可能参与ICF综合征的发生。MBD1作为DNA甲基化介导的转录抑制因子发挥作用。Nakao的研究小组报道，MBD1招募了组蛋白甲基转移酶SETDB1及其激活因子MCAF1(含MBD1的染色质相关因子)，导致IR转录抑制和异染色质形成，以组蛋白H3的第9个赖氨酸三甲基化为标志。在这种情况下，MBD1的SUMO化对于形成MBD1-MCAF1-SETDB1抑制复合体是重要的。研究还发现，MBD1和多梳蛋白在转录抑制和异染色质形成中的作用是重叠的。此外，另一种类型的MBD蛋白MeCP2的MBD结构域在Rett综合征中经常发生突变，大多数MBD突变失去了与甲基化DNA结合的能力。Nakao研究小组发现，一些MBD突变体保留了甲基化的DNA结合，表明存在尚未确定的发病机制。此外，在人类基因组的边界元件中，发现绝缘子结合蛋白CTCF与染色质重塑因子CHD8协同作用，导致增强子对H191IGF2印迹区域的封闭作用。这是绝缘体与表观遗传重塑有关的第一个证据。在小鼠ES细胞的神经分化过程中，PML小体和染色质中心明显重组，Oct3/4基因的组蛋白乙酰化和甲基化以及DNA甲基化在ES细胞、神经前体细胞和终末分化神经元的各个阶段进行了差异标记。较少