The relationship between spatial nuclear organization and stochastic gene expression

2001年夏天开始的NSF CAREER奖用于启动原核和真核生物中随机基因表达的研究计划。 通过这一努力支持的酵母研究结果指出了染色体定位对调节随机基因表达的重要性，从而提供了第一条线索，即空间组织可能在决定基因表达的随机特性方面发挥重要作用。在早期的随机基因表达研究中，细胞被认为是一个充分搅拌的系统，这种空间方面通常被忽略。继续这项工作的总体目标是使用芽殖酵母酿酒酵母作为模型系统来确定空间核组织与随机基因表达之间的关系。该项目的重点是以下具体目标：1。测量同一染色体上两个基因表达波动之间的相关性，作为基因间基因组距离的函数.测量当同一条染色体上的一个或多个基因座被募集到核周围时，同一条染色体上两个基因表达波动之间的相关性如何变化。在真实的时间内测量基因位点的三维位置与该基因在单细胞中的相应表达之间的时间相关性。这三个项目都涉及一个重要的数学和生物成分，反映了现代生物学的跨学科性质。例如：随机波动的概念起源于工程学科;需要数学方法来实现该过程;来自物理学的概念（例如扩散）提供了洞察力;并且通常来自计算机科学的代码使得能够进行大规模计算。作为教育工作的一部分，通过该项目培训的学生将获得由主要研究者开发的跨学科课程，这些课程弥合了孤立学科之间的差距。这些课程将通过大学广泛提供。

A NSF CAREER award that started in the Summer of 2001 was used to initiate a research program on stochastic gene expression in both prokaryotic and eukaryotic organisms. One result of the work on yeast supported through this effort pointed to the importance of chromosomal positioning for regulating stochastic gene expression, thereby providing the first clue that spatial organization might play an important role for determining the stochastic properties of gene expression. This spatial aspect had generally been ignored in the earlier studies on stochastic gene expression in which the cell was considered as a well-stirred system. The general objective of the continuation of this effort is to determine the relationship between spatial nuclear organization and stochastic gene expression using the budding yeast Saccharomyces cerevisiae as a model system. The project is focused on the following specific Aims:1. Measure the correlation between expression fluctuations of two genes on the same chromosome as a function of the genomic distance between the genes.2. Measure how the correlation between expression fluctuations of two genes on the same chromosome change as one locus or several loci on this chromosome are recruited to the nuclear periphery.3. Measure the temporal correlation between the three-dimensional position of a gene locus and the corresponding expression of this gene in single cells in real time. These three projects involve both a significant mathematical and biological ingredient reflecting the interdisciplinary nature of modern biology. For example; the concept of stochastic fluctuations originates from engineering disciplines; mathematical methods are needed to implement the procedures; concepts from physics, such as diffusion, provide insight; and often codes from computer sciences enable large scale calculations. As part of the educational effort, the students trained through this project will be provided with interdisciplinary courses developed by the principal investigator that bridge the gaps between the isolated disciplines. These courses will be offered widely through the university.