Structure function and evolution of yeast transcription networks

描述（由申请人提供）：所有细胞不断调整其基因表达程序以响应环境和遗传扰动。基因表达的变化是由一个复杂的调控网络介导的，其中转录调控是一个主要组成部分。细胞转录网络基本上调控着所有的生物过程，从发育到癌症和衰老。本研究的目标是开发新的理论和实验方法来系统地分析转录网络的结构、功能和进化，以酵母为模式生物。在之前授权期取得重大进展的基础上，我们将继续努力在基因组规模上重建酵母转录网络。为了了解网络结构的生理重要性，我们将定量分析基因组中所有转录因子缺失突变体在各种条件下的生长表型，并将全球基因表达程序与细胞的适应度联系起来。我们将扩大研究范围，纳入全基因组核小体定位信息，以更好地了解核小体定位与转录调控之间的关系。我们将系统地对不同酵母物种的转录回路进行比较分析，以得出控制它们进化的基本原理。总之，这些系统级的研究将揭示酵母系统之外转录网络的基本功能和进化限制和设计原则。此外，酵母转录调控的特定知识可以转移到包括人类在内的高等真核生物，因为许多生物过程是高度保守的。

DESCRIPTION (provided by applicant): All cells constantly adjust their gene expression programs in response to environmental and genetic perturbations. The changes in gene expression are mediated by a complex regulatory network, of which transcriptional regulation is a major component. Cellular transcription networks regulate essentially all biological processes, from development to cancer and aging. The goal of the proposed research is to develop novel theoretical and experimental approaches to systematically analyze the structure, function, and evolution of transcription networks, using yeast as a model organism. Building on the significant progress we have made in the previous granting period, we will continue our efforts to reconstruct yeast transcription networks at a genomic scale. To understand the physiological importance of the network structure, we will quantitatively analyze the growth phenotypes of the deletion mutants of all the transcription factors in the genome under a variety of conditions, and connect global gene expression program to the fitness of the cell. We will expand the scope of our study to incorporate genome- wide nucleosome positioning information, to better understand the relationship between nucleosome positioning and transcriptional regulation. We will systematically perform comparative analysis of transcriptional circuits in different yeast species, in order to derive basic principles governing their evolution. Together these systems-level studies will reveal the basic functional and evolutionary constraints and design principles of transcription networks beyond the yeast system. In addition, specific knowledge of transcriptional regulation in yeast can be transferred to higher eukaryotes including humans, since many biological processes are highly conserved. PUBLIC HEALTH RELEVANCE: Cellular transcription networks regulate essentially all biological processes, including development, cancer and aging. Mis-regulation of these processes leads to human diseases. A global understanding of the structure, function and evolution of the transcription networks in yeast will likely lead to general principles applicable to humans and have a significant impact on human health.