Role of Condensin in Gene Regulation and Heterochromatin assembly in C. elegans

凝缩蛋白在秀丽隐杆线虫基因调控和异染色质组装中的作用

• 批准号: 7629157
• 负责人: James Francis Carey
• 金额: $ 5.34万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629157
• 关键词: Affect; Aneuploidy; Animal Model; Antibodies; Architecture; Basic Science; Biochemical Genetics; Biological Assay; Caenorhabditis elegans; Cell division; Cells; Chromatin; Chromatin Structure; Chromosomal Instability; Chromosome Condensation; Chromosome Segregation; Chromosome Structures; Chromosome abnormality; Chromosomes; Co-Immunoprecipitations; Complex; Data; Development; Double-Stranded RNA; Ensure; Epigenetic Process; Eukaryota; Failure; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genome; Genome Stability; Genomic Instability; Goals; Health; Heterochromatin; Human; Lead; Link; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Medical; Meiosis; Mitosis; Mitotic; Molecular; Multiprotein Complexes; Organism; Pathway interactions; Pattern; Play; Positioning Attribute; Process; Proteins; RNA Interference; RNA Interference Pathway; Regulation; Research; Resistance; Role; Shapes; Small RNA; Structure; Temperature; Testing; Transgenes; Work; Yeasts; base; chromatin immunoprecipitation; chromatin modification; chromatin protein; condensin; daughter cell; histone modification; insight; loss of function; mutant; neuronal cell body; prevent; research study; retinal rods; tool; tumor; tumor progression

DESCRIPTION (provided by applicant): During every cell division, the genome must accurately replicate and segregate a complete set of chromosomes into each daughter cell. Failures in chromosome segregation and gene regulation have severe consequences for human health, since creating cells with an inappropriate chromosome number can lead to aneuploidy and chromosome instability. Chromosome structure also plays a key role in promoting accurate gene expression to avoid cancer progression. Therefore, it is of prime importance to understand the various mechanisms regulating chromosome structure, and the long-term goal of my research is to define the molecular machinery and mechanisms that govern chromosome structure to ensure genomic stability. Conserved multiprotein complexes known as condensins are key regulators of chromosome architecture, and increasing evidence suggests that condensins play broader roles than previously appreciated, including gene silencing. In preliminary results, it was unexpectedly discovered that condensin II physically interacts with proteins that are associated with chromatin-based silencing and required for transgene silencing phenomena. Thus, this proposal aims to test the hypothesis that the mitotic condensin II complex in Caenorhabditis elegans (C. elegans) cooperates with the RNA interference (RNAi) machinery and chromatin proteins to establish heterochromatin and mediate gene expression. Using biochemical and genetic approaches: (1) The apparent interactions between condensin II and RNAi and chromatin proteins will be confirmed. Moreover, condensin-interacting proteins will be tested to determine if they contribute to chromosome segregation and are required for condensin recruitment. (2) Transgene assays will be utilized to investigate whether condensin II is required for related forms of chromatin-based silencing. (3) It will determined if small RNAs associate with condensin II and are required for its functions in chromosome assembly. These studies will provide insights into how these conserved mechanisms ensure the accurate building, expression, and segregation of chromosomes and avoid the chromosomal abnormalities often observed in cancers.

描述（由申请人提供）：在每次细胞分裂期间，基因组必须准确复制并将一组完整的染色体分离到每个子细胞中。染色体分离和基因调控的失败对人类健康有严重的后果，因为产生具有不适当染色体数目的细胞可能导致非整倍性和染色体不稳定性。染色体结构在促进准确的基因表达以避免癌症进展方面也起着关键作用。因此，了解调节染色体结构的各种机制是至关重要的，我研究的长期目标是确定控制染色体结构的分子机制和机制，以确保基因组稳定性。保守的多蛋白复合物称为凝聚素是染色体结构的关键调节因子，越来越多的证据表明凝聚素发挥着比以前更广泛的作用，包括基因沉默。在初步结果中，意外地发现缩合蛋白II与与基于染色质的沉默相关并且是转基因沉默现象所需的蛋白质物理相互作用。因此，该提议旨在验证秀丽隐杆线虫（C.habditis elegans）中有丝分裂凝聚素II复合物的假设。elegans）与RNA干扰（RNAi）机制和染色质蛋白协作以建立异染色质并介导基因表达。利用生物化学和遗传学的方法：（1）证实缩合酶II和RNAi与染色质蛋白之间的明显相互作用。此外，将测试凝聚素相互作用蛋白以确定它们是否有助于染色体分离并且是凝聚素募集所需的。(2)将利用转基因测定来研究基于染色质的沉默的相关形式是否需要缩合蛋白II。(3)它将确定小RNA是否与凝聚素II相关，并且是其在染色体组装中的功能所必需的。这些研究将深入了解这些保守机制如何确保染色体的准确构建，表达和分离，并避免癌症中经常观察到的染色体异常。