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

基因组的稳定性对维持细胞活力和功能至关重要。然而，在与疾病相关的细胞（如癌细胞）或因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性。基于先前对基因组多样性的研究，以及在高度分化区域存在某些组蛋白修饰，我假设组蛋白标记，特别是H3K27me3，通过促进基因组不稳定性而促成了观察到的变异性。在这个项目中，我想通过对丝状真菌模式生物Zymoseptoria tritici、Fusarium graminearum和Neurospora crassa的比较研究，确定异染色质分布如何通过影响染色质的核相互作用和DNA损伤的发生来影响基因组的不稳定性。我将分析这三个物种中各组蛋白甲基转移酶的野生型和缺失突变体中异染色质组蛋白标记H3K9me3、H3K27me3、H3K36me3和H4K20me3的分布。利用chip测序，检测双链断裂和染色体构象捕获，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。该项目将对不同物种中染色质组织和基因组稳定性和基因组进化动力学的作用获得重要的新见解。这些发现对于理解具有高度基因组不稳定性和可变性的生物体或细胞（如植物、动物或人类病原体以及癌细胞）中DNA不稳定性的机制尤其重要。

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.