The effect of aneuploidy on cellular physiology and adaptation

描述（由申请人提供）：非整倍体，染色体拷贝数不均匀和异常的状态，是真核生物中经常观察到的基因组变异，是癌症的标志，被认为在癌症进化和耐药性发展中起重要作用。该项目的目标是利用细胞生物学、遗传学和基因组分析的创造性结合，对模式生物——出芽酵母酿酒酵母进行分析，以获得非整倍性如何影响基因组稳定性、细胞生理学和应激适应的基本见解。我们最近开发了几种新的方法来产生随机染色体化学计量的等基因非整倍体酵母菌株，并跟踪非整倍体群体的核型动力学。这些方法使我们对非整倍性与细胞胁迫之间的关系以及染色体拷贝数变异对基因表达和适合度的深刻影响做出了重要的观察。拟议的研究建立在这些发现的基础上，有四个具体目标。第一个目的是通过研究非整倍性对表观遗传调控机制的潜在影响，进一步了解非整倍性对基因表达的影响。第二个目标集中在为什么非整倍性有进一步促进染色体不稳定的趋势，导致核典型马赛克群体适应大范围的扰动。第三个目的是调查与非整倍体相关的共同应激状态的可能存在。最后一个目的是探索一种利用非整倍体和核型动力学的策略，这可能对治疗癌症或真菌感染有潜在的用处。

DESCRIPTION (provided by applicant): Aneuploidy, the state of having uneven and abnormal chromosome copy numbers, is a frequently observed genome variation in eukaryotes and is a hallmark of cancer thought to play important roles in cancer evolution and development of drug resistance. The goal of this project is to use a creative combination of cell biology, genetics and genomic analyses in the model organism, the budding yeast Saccharomyces cerevisiae, to gain fundamental insights into how aneuploidy affects genome stability, cellular physiology and stress adaptation. We have recently developed several new methods to generate isogenic aneuploid yeast strains with random chromosome stoichiometry and to follow karyotype dynamics in aneuploid populations. These methods have allowed us to make important observations on the relationship between aneuploidy and cellular stress, and the profound impact of chromosome copy number variation on gene expression and fitness. The proposed study builds upon these findings with four specific aims. The first aim attempts to further understand the consequence of aneuploidy on gene expression by investigating its potential effects on epigenetic regulatory mechanisms. The second aim focuses on the question of why aneuploidy has a tendency to promote further chromosome instability leading to karyotypically mosaic populations adaptive to a wide range perturbation. The third aim investigates the possible existence of a common stress state associated with aneuploidy. The last aim explores a strategy of exploiting aneuploidy and karyotype dynamics, which may be potentially useful for treating cancer or fungal infections.