How MeCP2 discriminates epigenetic marks is still a mystery

摘要 X染色体编码的“甲基CpG结合蛋白2”（MECP 2）在神经元中高度表达。 组织，并因其识别甲基-CpG（mCpG）表观遗传修饰而命名。的 MeCP 2对神经元和大脑发育的重要性通过MeCP 2 突变导致>90%的自闭症谱系障碍Rett综合征的诊断病例。 最近的基因组学研究提出了关于DNA序列全方位的重要问题 和蛋白质结合的碱基修饰类型。我们建议的研究旨在确定 核苷酸修饰类型特异性识别的分子机制， 序列和结合协同性，其融合以介导MeCP 2在染色质上的定位。我们 项目交错能量和结构分析，提出定量组装研究， 确定核苷酸修饰与局部和侧翼DNA序列的组合， 赋予高特异性MeCP 2结合，MeCP 2- DNA复合物的结构揭示， 在结合的靶位点之间存在差异，并决定MeCP 2如何与接头竞争 染色质上的组蛋白，随后定位于特定位点。我们的建议整合了 建立和新的定量和结构方法，探索如何结合这一关键 调节蛋白与染色质的相互作用启动了一系列的分子相互作用， 发展

Abstract The X chromosome coded `Methyl CpG binding protein 2' (MECP2) is highly expressed in neuronal tissues and named for its recognition of the methyl-CpG (mCpG) epigenetic modification. The importance of MeCP2 to neuronal and brain development is highlighted by the fact that MeCP2 mutations cause >90% of the diagnosed cases of the autism spectrum disorder Rett syndrome. Recent genomic studies have raised important questions regarding the full range of DNA sequences and types of base modifications bound by the protein. Our proposed studies seek to determine the molecular mechanisms underlying specific recognition of the type of nucleotide modification, DNA sequence, and binding cooperativity that meld to mediate localization of MeCP2 on chromatin. Our project interleaves energetic and structural analyses proposing quantitative assembly studies to determine the combinations of nucleotide modification with local and flanking DNA sequences that confer high specificity MeCP2 binding, the structure of MeCP2 - DNA complexes to reveal if differences exist among the bound target sites, and determine how MeCP2 competes with linker histones on chromatin and subsequently localizes to specific sites. Our proposal integrates established and novel quantitative and structural approaches to explore how binding of this key regulatory protein to chromatin initiates a cascade of molecular interactions that guides neuronal development.