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

描述（由申请人提供）：在每次细胞分裂期间，基因组必须准确地复制和分离一套完整的染色体到每个子细胞中。染色体分离和基因调控失败对人类健康造成严重后果，因为产生染色体数目不适当的细胞可导致非整倍体和染色体不稳定。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明确控制染色体结构的分子机制和机制，以确保基因组的稳定性。被称为凝聚蛋白的保守多蛋白复合物是染色体结构的关键调节因子，越来越多的证据表明，凝聚蛋白发挥的作用比以前所认识的更广泛，包括基因沉默。在初步结果中，意外地发现凝缩蛋白II与染色质沉默相关的蛋白质发生物理相互作用，这些蛋白质是转基因沉默现象所必需的。因此，本研究旨在验证秀丽隐杆线虫（Caenorhabditis elegans， C. elegans）有丝分裂凝缩蛋白II复合体与RNA干扰（RNA interference, RNAi）机制和染色质蛋白协同建立异染色质并介导基因表达的假说。利用生物化学和遗传学方法：(1)确认凝缩蛋白II与RNAi和染色质蛋白之间的明显相互作用。此外，凝缩蛋白相互作用蛋白将被测试，以确定它们是否有助于染色体分离和凝缩蛋白募集。(2)转基因试验将用于研究凝缩蛋白II是否需要相关形式的染色质沉默。(3)它将确定小rna是否与凝缩蛋白II相关联，并在染色体组装中发挥作用。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，并避免在癌症中经常观察到的染色体异常。

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.