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、染色质结构和高阶组织的调控。基因在细胞核内的位置和彼此之间的关系往往与它们的表达有关。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。作为一个理解基因定位的模型，我们关注的是基因在酿酒酵母中激活后从核质转移到核外周的分子机制。靶向核外周涉及与核孔复合物（NPC）的物理相互作用，并由顺式作用基因募集序列（GRSs）介导。GRSs的功能就像DNA邮政编码：它们是诱导与NPC相互作用和在核外围定位的必要和充分条件。此外，邮政编码赋予核外围基因的染色体间聚类。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类。我们已经确定了几个DNA邮政编码和一个蛋白质识别GRS I邮政编码介导靶向核周围和染色体间聚类。本文拟开展的研究将包括：1)确定GRS I DNA邮政编码介导靶向至核外周并促进转录的分子机制；2)确定GRS I DNA邮政编码介导靶向的全基因组范围；3)验证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.