How does chromatin structure influence nuclear localization of chromosomes and genome stability?

基因组的稳定性对维持细胞的活力和功能至关重要。然而，在与疾病相关的细胞(如癌细胞)或随着环境条件变化而迅速进化的生物体中，经常发现高度的基因组变异和不稳定。根据以前对基因组多样性和高度分化区域中存在某些组蛋白修饰的研究，我假设组蛋白标记，特别是H3K27me3，通过促进基因组不稳定而导致观察到的可变性。通过这个项目，我想确定异染色质分布是如何通过影响染色质的核相互作用和DNA损伤的发生来促进基因组不稳定的，这是通过对丝状真菌模式生物小麦酵母、禾谷镰刀菌和粗糙脉孢菌的比较研究来实现的。我将分析异染色质标记H3K9me3、H3K27me3、H3K36me3和H4K20me3在这三个物种各自的组蛋白甲基转移酶野生型和缺失突变体中的分布。利用芯片测序、双链断裂检测和染色体构象捕获，我将能够确定异染色质动力学及其对基因组稳定性和核染色质相互作用的影响。这个项目将获得对染色质组织和动态对不同物种的基因组稳定性和基因组进化的作用的重要的新见解。这些发现对于理解生物或细胞中DNA不稳定的机制特别相关，这些生物或细胞表现出高度的基因组不稳定和变异性，如植物、动物或人类病原体以及癌细胞。

Genome stability is essential to maintain cellular viability and function. However, a high degree of genome variation and instability is often found in cells associated to disease (e.g. cancer cells) or organisms that are rapidly evolving in response to changing environmental conditions. Based on previous studies on genome diversity and the presence of certain histone modifications in highly divergent regions, I hypothesize that histone marks, especially H3K27me3, contribute to the observed variability by promoting genome instability. With this project, I want to determine how heterochromatin distribution contributes to genome instability by influencing nuclear interaction of chromatin and the occurrence of DNA damage in a comparative study of the filamentous fungal model organisms Zymoseptoria tritici, Fusarium graminearum, and Neurospora crassa. I will analyze the distribution of heterochromatin histone marks H3K9me3, H3K27me3, H3K36me3, and H4K20me3 in wildtype and deletion mutants of the respective histone-methyltransferases in the three species. Using ChIP-sequencing, detection of double-strand breaks and chromosome conformation capture, I will be able to determine heterochromatin dynamics and their influence on genome stability and nuclear chromatin interactions. This project will gain important novel insights into the role of chromatin organization and dynamics for genome stability and genome evolution in different species. These findings will be especially relevant to understand mechanisms of DNA instability in organisms or cells that exhibit a high degree of genome instability and variability such as plant, animal, or human pathogens, as well as cancer cells.