Movement of regulated genes to the nuclear periphery

描述(申请人提供)：该项目的长期目标是了解基因表达调控和核亚结构之间的关系。最近的报道表明，在模式真核生物酿酒酵母中，基因在转录诱导后不久就会移动到核周，并与核孔复合体结合。具体目的1是利用单细胞检测基因表达调控来确定核周基因锚定与转录开启和关闭状态之间的关系。具体目标2是探索向核外移动是转录诱导基因的普遍属性的可能性。如果不是，重要的是要确定没有定位在核外围的转录活性基因是否会锚定在细胞核的其他地方，例如在核仁内。了解基因调控的这些和其他相关方面对于开发有效的人类疾病治疗方法是关键，因为转录调控不当往往导致先天性疾病和癌症。例如，神经退行性疾病脊髓小脑性共济失调7是由染色质修饰TFTC复合体的SCA7亚单位中的三核苷酸扩张引起的。这些研究将利用集成的方法，包括遗传、细胞生物学和生化分析，这在酿酒酵母模型系统中是可能的。这种有机体很容易被培养和操纵，这也使它成为为本科生提供研究机会的理想选择。公共卫生相关性：该项目的长期目标是了解基因表达调控和核亚结构之间的关系。了解基因调控的这些和相关方面对于开发有效的人类疾病治疗方法是关键，因为转录调控不当往往导致先天性疾病和癌症。

DESCRIPTION (provided by applicant): The long term objective of this project is to understand the relationship between the regulation of gene expression and nuclear substructure. Recent reports indicate that, soon after they are transcriptionally induced, genes in the model eukaryote Saccharomyces cerevisiae move to the nuclear periphery and associate with nuclear pore complexes. Specific Aim 1 is to use a single cell assay for regulated gene expression to determine the relationship between perinuclear gene anchoring and the ON and OFF transcriptional states. Specific Aim 2 is to explore the possibility that movement to the nuclear periphery is a universal property of transcriptionally induced genes. If not it will be important to determine whether transcriptionally active genes not anchored at the nuclear periphery become anchored elsewhere in the nucleus, for example within the nucleolus. Understanding these and other related aspects of gene regulation is key to the development of effective therapeutics for human diseases, since improperly regulated transcription is often responsible for congenital disorders and cancer. For example, the neurodegenerative disease spinocerebellar ataxia 7 results from a trinucleotide expansion in the SCA7 subunit of the chromatin modifying TFTC complex. These studies will take advantage of the integrated approach, including genetic, cell biological, and biochemical analyses, that is possible in the S. cerevisiae model system. The ease with which this organism can be grown and manipulated also makes it an ideal choice in providing research opportunities for undergraduate students. PUBLIC HEALTH RELEVANCE: The long-term objective of this project is to understand the relationship between the regulation of gene expression and nuclear substructure. Understanding these and related aspects of gene regulation is key to the development of effective therapeutics for human diseases, since improperly regulated transcription is often responsible for congenital disorders and cancer.