Analysis of Nematode Sex Determination

线虫性别测定分析

• 批准号: 8391191
• 负责人: BARBARA J MEYER
• 金额: $ 51.73万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391191
• 关键词: Accounting; Aneuploidy; Animal Model; Animals; Area; Behavior; Beryllium; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Caenorhabditis elegans; Cancerous; Cells; Chromosomal Instability; Chromosome Segregation; Chromosome Structures; Chromosomes; Complex; DNA Sequence Rearrangement; Defect; Development; Dosage Compensation (Genetics); Dose; Elements; Future; Gene Expression; Gene Expression Regulation; Gene Family; Gene Targeting; Genes; Genetic; Genetic Identity; Genetic Recombination; Genetic Transcription; Genome; Genome Stability; Genomic Instability; Goals; Homologous Gene; Human; Knowledge; Lead; Ligands; Link; Malignant Neoplasms; Mediating; Meiosis; Meiotic Recombination; MicroRNAs; Mitotic; Mitotic Chromosome; Molecular; Nematoda; Nuclear Hormone Receptors; Nuclear Pore Complex; Nuclear Receptors; Pathway interactions; Pattern; Pharmacotherapy; Play; Ploidies; Process; Proteins; RNA Interference; RNA Splicing; Receptor Gene; Regulatory Element; Relative (related person); Repression; Research; Resolution; Retinoic Acid Receptor; Retinoids; Role; Signal Pathway; Signal Transduction; Site; Specific qualifier value; Specificity; Switch Genes; Transcriptional Activation; Translating; Work; X Chromosome; autosome; condensin; gene repression; genome-wide; insight; leukemia; mRNA Precursor; male; member; promoter; protein complex; public health relevance; segregation; sex; sex determination; tumor

DESCRIPTION (provided by applicant): Dose-sensitive signals play essential roles in cell fate decisions during development. One area of our research investigates mechanisms by which small quantitative differences in molecular signals are translated into dramatically different developmental fates. One of our long-term goals is to dissect the quantitative signals and the genetic switch that specifies sexual fate in the nematode C. elegans. C. elegans determines sex by tallying X-chromosome number relative to the ploidy, the sets of autosomes (X:A signal). We showed that a set of genes on X, called X signal elements (XSEs), relays X-chromosome dose by repressing the activity of the sex determination switch gene xol-1 through both transcriptional and pre-mRNA mechanisms. Another set of genes called autosomal signal elements (ASEs) communicates ploidy by antagonizing the XSEs to activate xol-1. xol-1 specifies the male fate when active and the hermaphrodite fate when inactive. Our work investigates molecular mechanisms by which XSEs and ASEs antagonize each other to determine sex. One XSE is a nuclear hormone receptor (NHR) called SEX-1, a homolog of the retinoic acid receptor (RAR) gene family that participates in signaling pathways used for patterning and cellular differentiation in all metazoans. Disruptions in RARs are associated with human cancers, knowledge that has lead to the use of retinoids in the treatment of leukemias. Information gained from model organisms such as C. elegans about the genetic pathways in which NHRs function will provide an opportunity to discover other gene targets for drug therapy, which might be applicable to humans. A second long-term goal is understand the mechanism of X-chromosome dosage compensation, which equalizes X expression between the sexes. We defined a protein complex (DCC) that binds both X chromosomes of XX animals to repress X expression by half. Members of the complex also play essential roles in the compaction, resolution, and segregation of mitotic and meiotic chromosomes as well as the control of genetic recombination between homologous meiotic chromosomes. Not only is the protein complex essential for proper gene expression and viability, most components are essential for genome stability. Thus, studying dosage compensation will help us understand genomic instability caused by errors in chromosome segregation and disruption of meiotic recombination. We have identified cis-acting regulatory elements that target the X chromosome for repression by the DCC and discovered fundamental principles by which the DCC recognizes and binds X. Our future work will explore the connection between chromosome structure, DCC binding, and chromosome-wide gene repression.

描述（申请人提供）：剂量敏感的信号在开发过程中在细胞命运决策中起着重要作用。我们研究的一个领域调查了机制，通过这些机制，通过将分子信号的微量差异转化为截然不同的发育命运。我们的长期目标之一是剖析定量信号和指定线虫秀丽隐杆线虫中性命运的遗传转换。 C.秀丽隐杆线虫通过将X染色体的数量计数相对于倍体（x染色体）（X：A信号）来决定性。我们表明，X上的一组基因，称为X信号元件（XSE），通过通过转录和前MRNA机制抑制性别确定开关基因XOL-1的活性来中继X染色体剂量。另一组称为常染色体信号元件（ASE）的基因通过对抗XSE激活XOL-1来传达倍数。 XOL-1指定雄性命运在活跃时和雌雄同体命运时指定命运。我们的工作调查了XSE并互相拮抗以确定性别的分子机制。一个XSE是一种称为SEX-1的核激素受体（NHR），这是视黄酸受体（RAR）基因家族的同源物，它参与所有后生动物中用于图案和细胞分化的信号传导途径。 RAR中的破坏与人类癌症有关，这些知识导致类视黄素在治疗白血病中。从模型生物（例如秀丽隐杆线虫）获得的有关NHRS功能的遗传途径等模型生物中获得的信息，可以为发现其他可能适用于人类的药物疗法的基因靶标提供机会。第二个长期目标是了解X染色体剂量补偿的机制，该机制均衡性别之间的X表达。我们定义了一种蛋白质复合物（DCC），该蛋白质复合物结合了XX动物的两种X染色体，以将X表达抑制一半。该复合物的成员在有丝分裂和减数分裂染色体的压实，分辨率和隔离以及控制同源减数分裂染色体之间的遗传重组中也起着重要作用。蛋白质复合物不仅对于适当的基因表达和生存能力必不可少，而且大多数组件对于基因组稳定性至关重要。因此，研究剂量补偿将有助于我们理解染色体分离和减数分裂重组的破坏引起的基因组不稳定性。我们已经确定了针对X染色体以抑制DCC的顺式作用调节元件，并发现了DCC识别和结合X的基本原理。我们的未来工作将探索染色体结构，DCC结合和全染色体基因抑制之间的联系。