DNA zip codes and the spatial organization of the yeast genome

描述(申请人提供)：基因表达受转录因子、染色质结构和高级组织的调控。基因在细胞核内的位置以及彼此之间的相对位置往往与它们的表达相关。然而，控制基因在细胞核内定位的分子机制以及基因定位的功能意义尚不清楚。作为一个了解基因定位的模型，我们重点研究了酿酒酵母中基因在激活时从核质移动到核周的分子机制。靶向核外周涉及与核孔复合体(NPC)的物理相互作用，并由顺式作用的基因招募序列(GRS)介导。GRS的功能相当于DNA邮政编码：它们对于诱导与NPC的相互作用和在核外围的定位是必要的和充分的。此外，邮政编码还赋予了核边缘基因的染色体间聚集性。这表明酵母基因组编码其空间组织，顺式作用的DNA序列通过与NPC的相互作用控制基因的染色体间聚集。我们已经确定了几个DNA邮政编码和一个识别GRS I邮政编码的蛋白质，以介导针对核外围和染色体间聚集的靶向。拟议的研究将1)确定GRS I DNA邮政编码介导靶向核外周并促进转录的分子机制，2)确定GRS I邮政编码介导的靶向的全基因组范围，3)检验DNA邮政编码影响酵母基因组全球组织的假设。

DESCRIPTION (provided by applicant): 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. However, the molecular mechanisms that control gene positioning within the nucleus, and the functional significance of gene positioning, are unclear. As a model to understand gene positioning, we have focused on the molecular mechanisms by which genes move 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 Gene Recruitment Sequences (GRSs). GRSs function as DNA zip codes: they are necessary and sufficient to induce interaction with the NPC and localization at the nuclear periphery. Furthermore, zip codes confer interchromosomal clustering of genes at the nuclear periphery. This suggests that the yeast genome encodes its spatial organization and that cis-acting DNA sequences control interchromosomal clustering of genes through interaction with the NPC. We have identified several DNA zip codes and a protein that recognizes the GRS I zip code to mediate targeting to the nuclear periphery and interchromosomal clustering. The proposed studies will 1) determine the molecular mechanism by which the GRS I DNA zip code mediates targeting to the nuclear periphery and promotes transcription, 2) determine the genome-wide scope of GRS I zip code-mediated targeting and 3) test the hypothesis that DNA zip codes impact the global organization of the yeast genome.