Gene regulatory functions of condensin

凝缩蛋白的基因调控功能

基本信息

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
项目类别：
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

项目摘要

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.

项目概要染色质结构和组织对于建立适合发育的基因表达至关重要每种细胞类型的程序，这些过程中的异常会导致发育异常和疾病。线虫 C. elegans 中 X 染色体基因表达的调控是一个很好的模型破译调节染色质结构、核结构和基因的分子机制表达。在这种生物体中，一种称为凝缩蛋白的蛋白质复合物结合 XX 的两条 X 染色体雌雄同体下调基因表达两倍，从而平衡 X 连锁基因表达两性之间。凝缩蛋白因其在有丝分裂染色体压缩中的功能而闻名，但 C. 线虫剂量补偿为我们提供了揭示其间期作用的机会。凝聚素在多个层面上影响 X 染色体结构，包括组蛋白的翻译后修饰，染色体拓扑和压缩的改变，以及将染色体束缚在核外围。这些功能需要与其他细胞机制合作，例如组蛋白修饰剂和蛋白质核层。最近的证据表明凝缩蛋白也与核 RNAi 合作重塑 X 染色体并抑制其基因的机制。拟议的研究将检验凝缩蛋白、核 RNAi、组蛋白修饰剂和核纤层之间的相互作用，并定义如何这些过程相互配合，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相结合，以识别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，凝缩蛋白结合和其他抑制机制的相对贡献将是裸露。最近报道了小头畸形和各种疾病患者的凝缩蛋白突变癌症。因此，该项目的研究结果可能与人类健康直接相关。