Gene regulatory functions of condensin

凝缩蛋白的基因调控功能

• 批准号: 10263216
• 负责人: Gyorgyi Csankovszki
• 金额: $ 30.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263216
• 关键词: ATP phosphohydrolase; ATPase Domain; Address; Affect; Architecture; Auxins; Binding; Bioinformatics; Biological Assay; Caenorhabditis elegans; Catalytic Domain; Cell Nucleus; Cells; Chromatin Fiber; Chromatin Structure; Chromosome Condensation; Chromosome Structures; Chromosomes; Complex; Data; Defect; Development; Disease; Dosage Compensation (Genetics); Embryonic Development; Eukaryota; Fluorescence Microscopy; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genome; Genomic approach; Genomics; Goals; Health; Hermaphroditism; Hi-C; Histones; Human; Individual; Interphase; Lead; Link; Lysine; Maintenance; Malignant Neoplasms; Mediating; Methods; Microcephaly; Microscopy; Mitotic; Mitotic Chromosome; Modeling; Modification; Molecular; Molecular Machines; Mutate; Mutation; Nematoda; Nuclear; Nuclear Lamina; Nuclear Proteins; Nucleosomes; Organism; Pathway interactions; Patients; Point Mutation; Post-Translational Protein Processing; Process; RNA Interference; Regulation; Regulator Genes; Reporting; Repression; Research; Resolution; Role; Structural defect; Structure; System; Techniques; Testing; Time; Work; X Chromosome; Yeasts; base; cell type; chromosome conformation capture; condensin; defined contribution; experimental study; gene repression; histone modification; mRNA sequencing; male; mutant; precise genome editing; programs; protein complex; 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. Regulation of X chromosome gene expression in the nematode C. elegans is an excellent model to decipher the molecular mechanisms that regulate chromatin structure, nuclear architecture and gene expression. In this organism, a protein complex called condensin binds both X chromosomes of XX hermaphrodites to downregulate gene expression two-fold thereby equalizing X-linked gene expression between the sexes. Condensin is best known for its function in mitotic chromosome compaction, but C. elegans dosage compensation provides us with an opportunity to uncover its interphase roles. Condensin affects X chromosome structure on multiple levels, including posttranslational modifications of histone, alterations in chromosome topology and compaction, and tethering the chromosome to the nuclear periphery. These functions require cooperation with other cellular machinery, such as histone modifiers and proteins of the nuclear lamina. Recent evidence indicates that condensin also cooperates with the nuclear RNAi machinery to remodel the X chromosome and repress its genes. The proposed research will examine the interactions between condensin, nuclear RNAi, histone modifiers, and the nuclear lamina, and define how these processes cooperate to establish and then maintain repression of the X chromosomes. State-of-the art superresolution microscopy methods will be combined with genomic methods and bioinformatics to identify chromosome structure changes that are causally involved in gene repression. Using precise genome editing techniques, the relative contributions of condensin binding and the other repressive mechanisms will be uncovered. Condensin mutations have recently been reported in patients with microcephaly and various cancers. Therefore, findings from this project may become directly relevant to human health.

项目总结 染色质的结构和组织是建立适合发育的基因表达的关键 每种细胞类型的程序，以及这些过程中的异常会导致发育异常和 疾病。线虫X染色体基因表达调控是研究线虫X染色体基因表达的良好模型 破译调控染色质结构、核结构和基因的分子机制 表情。在这种生物体中，一种名为凝集素的蛋白质复合体结合了XX的两条X染色体 雌雄同体将基因表达下调两倍，从而平衡X连锁基因的表达 在两性之间。凝聚素最为人所知的是它在有丝分裂染色体紧凑中的作用，但C. 秀丽的剂量补偿为我们提供了一个揭示其间期作用的机会。冷凝 在多个水平上影响X染色体结构，包括组蛋白的翻译后修饰， 染色体拓扑和紧凑的改变，并将染色体拴在核周。 这些功能需要与其他细胞机制合作，如组蛋白修饰物和 核膜。最近的证据表明，凝聚素也与核RNAi合作 重塑X染色体并抑制其基因的机制。拟议的研究将审查 凝聚素、核RNAi、组蛋白修饰物和核层之间的相互作用，并定义如何 这些过程共同建立并维持对X染色体的抑制。最先进的 超分辨显微镜方法将与基因组方法和生物信息学相结合，以鉴定 与基因抑制密切相关的染色体结构变化。使用精确的基因组编辑 技术，凝聚素结合和其他抑制机制的相对贡献将是 没有遮盖物。凝聚素突变最近被报道在小头畸形和各种不同疾病的患者中 癌症。因此，该项目的研究结果可能与人类健康直接相关。