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千个基因，这些基因必须适当表达以实现正常的细胞功能。对全基因组转录控制的机制细节的透彻理解是重要的，因为数十种转录因子与包括癌症在内的许多人类疾病的病因学有关。转录因子及其功能机制在酵母和哺乳动物之间是高度保守的。该建议的目的是产生一个全基因组，详细的，系统的分子在特定的生理反应过程中的酵母转录调控的理解。功能基因组学方法将被用来研究酵母基因组在热休克和稳定期应激反应过程中的转录重编程。对于在酵母中介导应激反应的选定转录因子，将使用多种方法确定其下游靶标。将确定染色质结构和结合位点复杂性对转录特异性的相对影响。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。他们将致力于确定功能转录调控网络的基础上的全球反应，以及确定顺式调控元件和染色质结构方面，赋予特异性。将对调控网络进行建模、实验验证并扩展以解释全球转录谱。这项工作将测试关于全基因组转录调控的几个假设，包括i）全球转录程序可以根据其复合转录途径和由单个转录调控因子介导的网络来重建ii）转录特异性通过顺式调控元件和启动子处的局部染色质结构的组合来实现，iii）多亚基复合物的不同成员在介导转录应答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，该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.