Gene Repression in Fragile X Syndrome

脆性 X 综合征的基因抑制

• 批准号: 6638040
• 负责人: HOWARD CEDAR
• 金额: $ 7.5万
• 依托单位: HEBREW UNIVERSITY OF JERUSALEM
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-21 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638040
• 关键词: DNA methylation; DNA replication; acetylation; alleles; behavioral genetics; cell fusion; chromatin; conformation; developmental genetics; disease /disorder model; embryo /fetus tissue /cell culture; fragile X syndromes; gene expression; gene induction /repression; genetic mapping; genetic regulatory element; genetically modified animals; histones; laboratory mouse; nucleic acid repetitive sequence; nucleoproteins; protein structure; transcription factor; transposon /insertion element

DESCRIPTION: (Adapted from the applicant?s description) Fragile X syndrome is caused by molecular defects in the structure and expression pattern of the FMR1 gene on the X chromosome. It is fairly well accepted that CGG repeat expansion leads to DNA methylation which then inhibits FMR1 activity, but very little is known about how this occurs. In order to decipher this mechanism, the investigators will use transgenic mice and embryonic cell culture systems. Studies on the cis acting elements and trans acting factors which regulate normal DNA methylation in the early embryo will form the basis for investigating the aberrant factors which bring about faulty methylation at the FMR1 locus. Studies on chromatin structure will be aimed at explaining how DNA methylation actually causes transcriptional inhibition. Another structural parameter which is affected in fragile X syndrome is DNA replication timing. Using FISH technology, the investigators plan to elucidate the mechanism which causes the FMR1 region to replicate so late in the cell cycle, and thus understand how this brings about regional repression. Unlike other genetic diseases, the molecular changes in fragile X syndrome are epigenetic in nature, so that once these mechanisms have been better defined, it should be possible to design new strategies for reactivating FMR1, thereby reversing the molecular defect.

描述：（改编自申请人的描述）脆性 X 综合征 是由结构和表达模式的分子缺陷引起的 X染色体上的FMR1基因。人们普遍认为 CGG 重复 扩增导致 DNA 甲基化，然后抑制 FMR1 活性，但非常 人们对这种情况如何发生知之甚少。为了破译这个机制， 研究人员将使用转基因小鼠和胚胎细胞培养系统。 调节顺式作用元件和反式作用元件的研究 早期胚胎中正常的DNA甲基化将构成 研究导致错误甲基化的异常因素 FMR1 基因座。对染色质结构的研究旨在解释如何 DNA甲基化实际上会导致转录抑制。 脆性 X 综合征受影响的另一个结构参数是 DNA 复制时间。研究人员计划利用 FISH 技术 阐明导致 FMR1 区域如此晚复制的机制 细胞周期，从而了解这如何带来区域抑制。 与其他遗传病不同，脆性 X 综合征的分子变化是 本质上是表观遗传，因此一旦这些机制得到更好的定义， 应该可以设计新的策略来重新激活 FMR1，从而 逆转分子缺陷。