DNA zip codes and the spatial organization of the yeast genome

项目摘要 基因表达受转录因子、染色质结构和更高级的调控 组织。基因在细胞核内的位置和相互之间的位置通常是相互关联的 他们的表情。控制基因在细胞核内定位的分子机制是 很大程度上是未知的。作为基因定位的模型，我们通过以下方式重点研究了分子机制 在酵母菌中，哪些基因在激活后从核质重新定位到核周 酿酒。靶向核周涉及到与核孔的物理相互作用 复杂(NPC)，并由既必要又充分的顺式作用DNA邮政编码调节 诱导与鼻咽癌的相互作用和在核外围的定位。这样的邮政编码也 在核周赋予基因染色体间聚集性。我们已经确定了一些 与这些邮政编码结合并介导靶向核外周的转录因子。这 这表明控制基因定位是转录因子未被认识到的功能， 顺式作用转录因子结合位点是一种控制空间组织的遗传手段 在基因组中。 拟议的研究将1)确定GCN4 Tf介导的分子机制 针对核周和染色体间聚集性，2)全面鉴定Tf和 影响基因定位的DNA结合蛋白，以及3)检验Tf在空间上和 从功能上划分酵母基因组。

Project Summary Gene expression is regulated by transcription factors, chromatin structure and higher order organization. The positioning of genes within the nucleus and with respect to each other often correlates with their expression. The molecular mechanisms that control gene positioning within the nucleus are largely unknown. As a model for gene positioning, we have focused on the molecular mechanisms by which genes reposition from the nucleoplasm to the nuclear periphery upon activation in Saccharomyces cerevisiae. Targeting to the nuclear periphery involves a physical interaction with the nuclear pore complex (NPC) and is mediated by cis-acting DNA zip codes that are both necessary and sufficient to induce interaction with the NPC and localization at the nuclear periphery. Such zip codes also confer interchromosomal clustering of genes at the nuclear periphery. We have identified a number of transcription factors that bind to these zip codes and mediate targeting to the nuclear periphery. This suggests that controlling gene positioning is an unappreciated function of transcription factors and that cis-acting transcription factor binding sites represent a genetic means to control the spatial organization of the genome. The proposed studies will 1) determine the molecular mechanism by which the Gcn4 TF mediates targeting to the nuclear periphery and interchromosomal clustering, 2) comprehensively identify TFs and DNA binding proteins that impact gene positioning, and 3) test the hypothesis that TFs spatially and functionally compartmentalize the yeast genome.