Role of DNA localization in regulating transcription

DNA的亚核定位在所有真核生物中都受到高度调控，并对转录和染色质结构具有重要但知之甚少的影响。DNA定位到核外周在建立转录抑制中具有明显的作用(Fisher和Merkenschlager，2002)。我对酿酒酵母的研究表明，某些基因在激活时也被招募到核外围，并且定位到外围会促进转录激活(Brickner和Walter，2004)。对酵母的全基因组研究表明，许多转录活性基因定位于核周(Casolari等人，2004年)。这种现象在酵母和哺乳动物之间可能是保守的；在小鼠中，_-珠蛋白基因座的转录激活也发生在核外围(Ragoczy等人，2006年)。我的实验室扩展了这些研究，我们发现，核外周的基因募集是最近转录的一种细胞记忆形式，标记了最近被抑制的基因，以促进更快的重新激活。 这个提议的最终目的是理解细胞生物学中的两个基本问题：1)细胞核在空间上是如何组织的，2)这种组织是如何影响转录的？我们将重点研究INO1和GAL1基因在酿酒酵母中向核外的动态募集。这些都是经过招募的基因的最典型的例子。酵母提供了分子遗传学和生物化学的强大结合，并将为研究这一过程提供一个理想的模型系统。我们将确定细胞用来控制基因定位的分子机制。我们还将定义转录记忆的一般性、特性和分子机制。最后，我们将检验基因定位在核外周的功能作用(S)。

The subnuclear localization of DNA is highly regulated in all eukaryotes and has important but poorly understood effects on transcription and chromatin structure. The localization of DNA to the nuclear periphery has a clear role in establishing transcriptional repression (Fisher and Merkenschlager, 2002). My studies in Saccharomyces cerevisiae reveal that certain genes are also recruited to the nuclear periphery upon activation and that localization to the periphery promotes transcriptional activation (Brickner and Walter, 2004). Genome-wide studies in yeast indicate that many transcriptionally active genes localize at the nuclear periphery (Casolari et al., 2004). This phenomenon may be conserved between yeast and mammals; trancriptional activation of the _-globin locus in mice also occurs at the nuclear periphery (Ragoczy et al., 2006). My lab has extended these studies and we have discovered that gene recruitment to the nuclear periphery serves as a form of cellular memory of recent transcription, marking recently repressed genes to promote more rapid reactivation. The ultimate objective of this proposal is to understand two fundamental questions in cell biology: 1) how is the nucleus spatially organized and 2) how does this organization affect transcription? We will focus on the dynamic recruitment of the INO1 and GAL1 genes to the nuclear periphery in Saccharomyces cerevisiae. These are the best characterized examples of genes that undergo recruitment. Yeast offers a powerful combination of molecular genetics and biochemistry and will provide an ideal model system for studying this process. We will determine the molecular mechanisms used by cells to control the localization of genes. We will also define the generality, properties and molecular mechanism of transcriptional memory. Finally, we will test the functional role(s) of gene localization at the nuclear periphery.7.