Analysis of genome wide transcriptional control in yeast

描述(由申请人提供)： 生物体的基因组编码数以千计的基因，这些基因必须得到适当的表达，才能实现正常的细胞功能。彻底了解全基因组转录控制的机制细节是重要的，因为数十个转录因子与包括癌症在内的许多人类疾病的病因学有关。转录因子及其作用机制在酵母和哺乳动物之间高度保守。这项建议旨在产生一个全基因组的，详细的和系统的分子理解酵母在特定的生理反应期间的转录调控。功能基因组学方法将被用来研究酵母基因组在对热休克和稳定期胁迫的反应中的转录重编程。对于在酵母中介导应激反应的选定转录因子，其下游靶标将使用各种方法来确定。染色质结构和结合部位复杂性对转录特异性的相对影响将被确定。同时，我们将应用各种计算方法来组织、分析和解释大量的结果数据。他们将致力于识别全球反应背后的功能性转录调控网络，以及识别赋予特异性的顺式调控元件和染色质结构的各个方面。将对调控网络进行建模、实验验证和扩展，以解释全球转录图谱。这项工作将检验关于全基因组转录调控的几个假说，包括：i)全球转录程序可以根据它们由单个转录调控因子介导的复合转录途径和网络来重构；ii)转录特异性是通过顺式调控元件和启动子上的局部染色质结构的组合来实现的；iii)多亚单位复合体的不同成员在介导转录反应中可能具有不同的作用。鉴于酵母和哺乳动物之间转录因子和机制的保守性，这一结果可能对理解和进一步研究人类基因组中的转录控制具有重要意义。

DESCRIPTION (provided by applicant): The genome of an organism encodes thousands of genes that must be appropriately expressed for normal cellular functioning. A thorough understanding of the mechanistic details of genome-wide transcriptional control is important, as dozens of transcription factors have been implicated in the etiology of many human diseases including cancer. Transcription factors, as well as their mechanisms of function, are highly conserved between yeast and mammals. This proposal is aimed at generating a genome-wide, detailed, and systematic molecular understanding of transcriptional regulation in yeast during specific physiological responses. A functional genomic approach will be used to study the transcriptional reprogramming of the yeast genome during the responses to heat shock and stationary phase stress. For selected transcription factors that mediate stress responses in yeast, their downstream targets will be determined using a variety of approaches. The relative influence of chromatin structure and binding site complexity on transcriptional specificity will be determined. Simultaneously, we will apply a variety of computational methods to organize, analyze and interpret the large body of resulting data. They will be directed towards identifying functional transcriptional regulatory networks underlying global responses, as well as identifying cis-regulatory elements and aspects of chromatin structure that confer specificity. Regulatory networks will be modelled, experimentally validated, and extended to explain global transcriptional profiles. This work will test several hypotheses about genome-wide transcriptional regulation, including i) global transcriptional programs can be reconstructed in terms of their composite transcriptional pathways and networks mediated by individual transcriptional regulators ii) transcriptional specificity is achieved through a combination of cis-regulatory elements and local chromatin structure at promoters, iii) different members of multi-subunit complexes may have distinct roles in mediating transcriptional responses. Given the conservation of transcription factors and mechanisms between yeast and mammals, the results are likely to be significant in understanding and further studying transcriptional control in the human genome.