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.

项目摘要 染色质结构和组织对于建立发育中适当的基因表达至关重要 每种细胞类型的程序，以及这些过程中的畸变导致发育异常和 疾病。 X染色体基因表达在线虫C.秀丽隐杆线虫中的调节是一个极好的模型 解解调节染色质结构，核结构和基因的分子机制 表达。在这个生物体中，一种称为冷凝蛋白的蛋白质复合物结合了xx的两个X染色体 雌雄同体下调基因表达两倍，从而平等x连接基因表达 在性别之间。冷凝素以其在有丝分裂染色体压实中的功能而闻名，但C。 秀丽隐杆线剂量补偿为我们提供了揭示其相间角色的机会。冷凝蛋白 在多个层面上影响X染色体结构，包括组蛋白的翻译后修饰， 染色体拓扑和压实的改变，并将染色体绑定到核周围。 这些功能需要与其他细胞机械合作，例如组蛋白修饰剂和蛋白质 核薄片。最近的证据表明，冷凝蛋白也与核RNAi合作 重塑X染色体并抑制其基因的机械。拟议的研究将研究 冷凝蛋白，核RNAi，组蛋白修饰剂和核层之间的相互作用，并定义如何 这些过程合作以建立并维持对X染色体的抑制。最先进的 超分辨率显微镜方法将与基因组方法和生物信息学结合使用，以鉴定 染色体结构的变化与基因抑制有关。使用精确的基因组编辑 技术，冷凝蛋白结合的相对贡献和其他抑郁机制将是 裸露。最近已经报道了小头畸形患者和不同 癌症。因此，该项目的发现可能与人类健康直接相关。