Chromatin structures influencing the dynamics of nucleosome remodeling

基因调控的一个持久的谜团是染色质组织，可靠地包装真核DNA，如何能够同时是透明的，以允许调控因子的访问。近年来，人们发现了一些酶，它们可以根据细胞内外的信号改变染色质的结构，使染色质呈现出高度动态的结构。染色质重塑酶在核小体阵列水平上将ATP水解与染色质结构的改变偶联。组蛋白尾部的翻译后修饰与不同的染色质状态和DNA可及性相关。蛋白质组学分析的最新进展揭示了核小体核心的新修饰，其中许多修饰位于组蛋白-DNA界面。关于这些修饰的作用知之甚少，但有几种修饰涉及调节染色质重塑，这表明组蛋白修饰和核小体重塑在调节染色质动力学方面存在密切联系。然而，仍然缺乏详细的分析和功能测试。(i)我建议在体内筛选，以确定组蛋白修饰及其组合，调节染色质动力学。(ii)我们希望解决染色质动力学的机械基础。ATP依赖性重塑通过不断移动核小体产生可接近的DNA，还是它们需要额外的信号才能导致局部核小体重塑的受调控复合物？(iii)重塑复合物在不同的染色质高级结构中是否同样有效？或者，染色质的不同压缩状态需要特殊的复合物？

One of the persistent enigmas of gene regulation is how the chromatin organisation, which reliably packages eukaryotic DNA, can at the same time be transparent to allow access of regulatory factors. Recent years have witnessed the discovery of enzymes modifying the structure of chromatin in response to cell-internal and -external cues, rendering chromatin a highly dynamic structure. Chromatin remodeling enzymes couple ATP hydrolysis to alterations of the chromatin structure at the level of the nucleosomal-array. Post-translational modifications of the histone tails are correlated with distinct chromatin states and DNA accessibility. The recent advances in proteomic analyses revealed novel modifications in the nucleosome core, many of which are positioned at the histone-DNA interface. Little is known about the role of these modifications, but several modifications are implicated to modulate chromatin remodeling, suggesting an intimate link between histone modifications and nucleosome remodelers in modulating chromatin dynamics. However, detailed analysis and functional testing is still lacking. (i) I propose an in vivo screen, to identify histone modifications and their combinations that modulate chromatin dynamics. (ii) We want to address the mechanistical basis of chromatin dynamics. Do ATP-dependent remodeler generate accessible DNA by constantly moving nucleosomes or are they regulated complexes that required additional signals that lead to localized nucleosome remodeling? (iii) Do remodeling complexes work similarly well in different higher order structures of chromatin? Or are specialized complexes required for different compaction states of chromatin?