Role of DNA localization in regulating transcription

DNA 定位在转录调控中的作用

• 批准号: 7489229
• 负责人: Jason Hays Brickner
• 金额: $ 5.26万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489229
• 关键词: Affect; Biochemistry; Biological Models; Cell Nucleus; Cells; Cellular biology; Chromatin Structure; Chromosome Mapping; DNA; Eukaryota; Eukaryotic Cell; Genes; Genetic Transcription; Genome; Globin; Localized; Mammals; Memory; Molecular; Molecular Genetics; Mus; Nuclear; Principal Investigator; Process; Property; Recruitment Activity; Role; Saccharomyces cerevisiae; Testing; Transcriptional Activation; Yeasts; abstracting; gene repression; programs

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.

DNA的亚核定位在所有真核生物中都受到高度调节，并且对转录和染色质结构具有重要但知之甚少的影响。DNA定位于核周边在建立转录抑制中具有明确的作用（Fisher和Merkenschlager，2002）。我在酿酒酵母中的研究表明，某些基因在激活时也被募集到核周边，并且定位到周边促进转录激活（Brickner和Walter，2004）。酵母中的全基因组研究表明，许多转录活性基因定位于核周边（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;小鼠中β-珠蛋白基因座的转录激活也发生在核外周（Ragoczy et al.，2006年）。我的实验室已经扩展了这些研究，我们发现，基因募集到核周边作为一种形式的细胞记忆最近的转录，标记最近压抑的基因，以促进更快的重新激活。 这个提议的最终目标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）这种组织如何影响转录？我们将重点关注酿酒酵母中INO 1和GAL 1基因向核周边的动态募集。这些是经历募集的基因的最佳表征的例子。酵母提供了分子遗传学和生物化学的强大组合，并将为研究这一过程提供理想的模型系统。我们将确定细胞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，性质和分子机制。最后，我们将测试基因定位在核周围的功能作用。