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）：基因表达的调节对于健康发育和疾病都至关重要。多细胞生物的大多数体细胞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取不同的细胞命运。基因表达的异常调节会导致发育缺陷和癌症等疾病。剂量补偿是基因调控的一种特殊形式，影响整个染色体上的许多或大多数基因，以平衡性别之间的基因表达。在秀丽隐杆线虫中，剂量补偿是通过类凝缩蛋白剂量补偿复合物 (DCC) 来完成的，该复合物结合 XX 雌雄同体的两条 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过程中包装和分离染色体的作用而闻名。然而，来自多个系统的证据表明凝缩蛋白也参与基因表达的调节。 DCC 以及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如何在机制上相关。该提案旨在阐明蠕虫剂量补偿过程中凝缩蛋白作用的机制，在细胞从可塑性向分化转变时如何建立，以及随后如何维持抑制。该提案测试了剂量补偿功能涉及通过招募染色质修饰复合物在剂量补偿 X 染色体上放置一组染色质标记的假设。这些染色质修饰建立了一个染色质环境，该环境抑制 RNA 聚合酶 II 结合，并导致聚合酶在早期延伸过程中停滞。该提案还旨在通过研究转录机制在剂量补偿过程中如何受到影响来阐明转录调控机制。最后，该提案还研究了 DCC 介导的抑制是如何启动和维持的，通过研究剂量补偿介导的染色质标记在具有分化缺陷的各种突变体中出现的时间，通过研究触发剂量补偿的基因在早期发育中如何受到调节，并在初始敏感期后使用条件突变体关闭 DCC 功能。