The gene regulatory functions of condensin

凝缩蛋白的基因调控功能

• 批准号: 10621514
• 负责人: Gyorgyi Csankovszki
• 金额: $ 37.64万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621514
• 关键词: Affect; Binding; Bioinformatics; Biological Process; Caenorhabditis elegans; Chromatin Fiber; Chromatin Loop; Chromatin Structure; Chromosome Condensation; Chromosome Segregation; Chromosome Structures; Chromosomes; Complex; Development; Disease; Dosage Compensation (Genetics); Gene Expression; Gene Expression Regulation; Genes; Genome; Genomics; Goals; Health; Hermaphroditism; Histones; Human; Interphase; Lead; Link; Malignant Neoplasms; Mediating; Methods; Microcephaly; Microscopy; Mitosis; Mitotic; Mitotic Chromosome; Molecular Machines; Mutation; Nuclear; Organism; Patients; Phosphorylation; Post-Translational Protein Processing; Process; Proteins; Regulation; Regulator Genes; Reporting; Research; Role; Sex Chromosomes; Techniques; Tissues; X Chromosome; Yeasts; cell type; condensin; gene repression; histone modification; precise genome editing; programs; sex

PROJECT SUMMARY Chromatin structure and organization are critical to establishing developmentally appropriate gene expression programs for each cell type, and aberrations in these processes lead to developmental abnormalities and disease. Our research program’s long-term goal is to define how a specialized molecular machine called condensin can restructure chromosomes to regulate genes in interphase as well as to promote chromosome segregation in mitosis. Condensin mutations have been reported in patients with microcephaly and various cancers. Therefore, findings from this project will have direct relevance to human health. Condensin complexes are conserved from yeast to human, and while their roles in mitosis are relatively well defined, their function in interphase gene regulation is not well understood. Regulation of X chromosome-wide gene expression in C. elegans provides us with an opportunity to uncover condensin’s interphase roles. In this organism, in a process called sex chromosome dosage compensation, a specialized condensin complex binds both X chromosomes of XX hermaphrodites to downregulate gene expression by half thereby equalizing X-linked gene expression between the sexes. Condensin-mediated gene repression involves altering X chromosome structure on multiple levels, including posttranslational modifications of histones, looping of the chromatin fiber, chromosome compaction, and nuclear organization. The first major project will determine how mutations in conserved domains affect condensin’s interphase roles compared to its mitotic roles. The effect of the phosphorylation, which is known to modulate condensin’s activity in mitosis, will also be investigated. The second project centers on the roles of histone modifiers which cooperate with condensin in the process of dosage compensation. These histone modifiers perform additional functions in the germline. The project will characterize the dual functionality of this cellular machinery to reveal how the same activity can be co-opted to fulfill different biological functions in different tissues. The third project examines how developmental regulators can coordinate sex chromosome dosage compensation with developmental transitions. Defining the regulation of key dosage compensation proteins at two key transitions, loss of the pluripotent state and then terminal differentiation, will reveal the mechanistic link between these processes. Precise genome editing techniques and tissue and developmental stage-specific protein depletion techniques will be employed to reveal the mechanism of action and regulation of condensin in gene regulation. State-of-the art microscopy techniques will be combined with genomic methods and bioinformatics to identify chromosome and chromatin structure changes that are linked to gene repression.

项目摘要 染色质的结构和组织是建立发育适当的基因表达的关键 每种细胞类型的程序，在这些过程中的畸变导致发育异常， 疾病我们的研究计划的长期目标是确定一个专门的分子机器， 凝聚素可以重组染色体，调控染色体间期基因，促进染色体 有丝分裂中的分离。据报道，在患有小头畸形和各种 癌的因此，该项目的发现将与人类健康直接相关。凝聚素复合物 从酵母到人类都是保守的，虽然它们在有丝分裂中的作用相对明确，但它们在 间期基因调控还不清楚。C. X染色体全基因表达调控 elegans为我们提供了一个机会来揭示凝聚素的相间作用。在这个生物体中， 称为性染色体剂量补偿，一种专门的凝聚素复合物结合两条X染色体， XX两性人的基因表达下调一半，从而平衡X连锁基因表达 两性之间的差异凝聚蛋白介导的基因阻遏涉及改变X染色体上的结构。 多个水平，包括组蛋白的翻译后修饰，染色质纤维的成环， 染色体致密化和细胞核结构。第一个主要项目将确定突变如何在 保守结构域影响凝聚素的间期作用相比，其有丝分裂的作用。的影响 也将研究已知调节有丝分裂中凝聚素活性的磷酸化。的 第二个项目集中在组蛋白修饰剂的作用，它与凝聚素在这一过程中的作用。 剂量补偿这些组蛋白修饰剂在种系中执行额外的功能。该项目将 描述这种细胞机制的双重功能，以揭示相同的活动如何被选择， 在不同的组织中实现不同的生物学功能。第三个项目研究发展调节器如何 可以协调性染色体剂量补偿与发育转变。定义法规 关键剂量补偿蛋白在两个关键转变，多能状态的丧失， 差异，将揭示这些过程之间的机械联系。精确的基因组编辑技术 组织和发育阶段特异性蛋白质耗竭技术将被用来揭示 凝聚素在基因调控中的作用机制和调控。最先进的显微镜技术 将结合基因组学方法和生物信息学来鉴定染色体和染色质结构 与基因抑制有关的变化。