The Dosage Compensation Machinery of C. Elegans

线虫的剂量补偿机制

• 批准号: 8517740
• 负责人: Gyorgyi Csankovszki
• 金额: $ 29.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517740
• 关键词: Adopted; Affect; Appearance; Binding; Biochemical; C-terminal; Caenorhabditis elegans; Cells; Chromatin; Chromosome Segregation; Chromosomes; Complex; DNA Polymerase II; Data; Defect; Development; Disease; Dosage Compensation (Genetics); Dose; Down Syndrome; Embryo; Environment; Equilibrium; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Goals; Histone Deacetylase; Histone H4; Immunofluorescence Microscopy; Lead; Link; Location; Lysine; Malignant Neoplasms; Mediating; Meiosis; Microscopic; Mitosis; Mitotic Chromosome; Mutation; Nematoda; Organism; Pathway interactions; Play; Polymerase; Process; RNA; RNA Polymerase II; Regulation; Regulator Genes; Repression; Research; Resolution; Role; Serine; Somatic Cell; Staging; System; Testing; Time; Time Study; Transcriptional Regulation; X Chromosome; autosome; chromatin immunoprecipitation; chromatin modification; condensin; developmental plasticity; dosage; gene repression; genome-wide; histone methyltransferase; male; member; mutant; research study; sex; tool

DESCRIPTION (provided by applicant): Regulation of gene expression is critical to both healthy development and disease. Multicellular organisms contain the same genetic information in most of their somatic cells, yet each cell expresses a unique set of genes and adopts a distinct cell fate. Aberrant regulation of expression of genes leads to developmental defects and diseases such as cancer. Dosage compensation is a specialized form of gene regulation affecting many, or most, genes on entire chromosomes, to balance gene expression between the sexes. In the worm Caenorhabditis elegans, dosage compensation is accomplished by a condensin-like dosage compensation complex (DCC), which binds both X chromosomes in XX hermaphrodites, to halve gene expression. Condensin is best known for its role in packaging and segregating chromosomes during mitosis and meiosis. However, evidence from several systems indicates that condensin is also involved in the regulation of gene expression. How the DCC, and by extension condensin, regulates gene expression is not known. The long-term goals of this project is to decipher how the gene regulatory and mitotic chromosome segregation roles of condensin are mechanistically related. This proposal is aimed at elucidating the mechanism of condensin-action during worm dosage compensation, how it is established at the time when cells transition from plasticity to differentiation, and how repression is maintained subsequently. The proposal tests the hypothesis that dosage compensation function involves placing a set of chromatin marks on dosage compensated X chromosomes, via recruitment of chromatin modifying complexes. These chromatin modifications set up a chromatin environment, which inhibits RNA polymerase II binding as well causes polymerase to stall during early elongation. The proposal also aims to elucidate the mechanism of transcription regulation by studying how the transcription machinery is affected during dosage compensation. Finally, the proposal also investigates how DCC-mediated repression is initiated and maintained, by studying the timing of appearance of dosage compensation mediated chromatin marks in various mutants with defects in differentiation, by studying how the gene triggering dosage compensation is regulated in early development, and by turning off DCC function after the initial sensitivity period using conditional mutants.

描述（由申请人提供）：基因表达调控对健康发育和疾病都至关重要。多细胞生物在其大多数体细胞中含有相同的遗传信息，但每个细胞表达一组独特的基因并采用不同的细胞命运。基因表达的异常调控会导致发育缺陷和癌症等疾病。剂量补偿是一种特殊形式的基因调控，影响整个染色体上的许多或大多数基因，以平衡两性之间的基因表达。在秀丽隐杆线虫（Caenorhabditis elegans）中，剂量补偿是通过凝缩蛋白样剂量补偿复合体（DCC）完成的，该复合体结合XX雌雄同体中的两条X染色体，使基因表达减半。凝缩蛋白以其在有丝分裂和减数分裂中包装和分离染色体的作用而闻名。然而，来自几个系统的证据表明凝缩蛋白也参与基因表达的调节。DCC及其延伸凝缩蛋白如何调节基因表达尚不清楚。该项目的长期目标是破译凝缩蛋白的基因调控和有丝分裂染色体分离作用是如何机制相关的。本研究旨在阐明在蠕虫剂量补偿过程中凝缩作用的机制，它是如何在细胞从可塑性向分化过渡时建立的，以及随后抑制是如何维持的。该提案测试了剂量补偿功能的假设，即通过招募染色质修饰复合物，在剂量补偿的X染色体上放置一组染色质标记。这些染色质修饰建立了一个染色质环境，它抑制RNA聚合酶II的结合，并导致聚合酶在早期伸长期间停滞。本提案还旨在通过研究在剂量补偿过程中转录机制如何受到影响来阐明转录调控的机制。最后，该提案还研究了DCC介导的抑制是如何启动和维持的，通过研究各种有分化缺陷的突变体中剂量补偿介导的染色质标记的出现时间，通过研究触发剂量补偿的基因在早期发育中如何被调节，以及通过使用条件突变体在初始敏感期后关闭DCC功能。