Analysis of Nematode Sex Determination

线虫性别测定分析

• 批准号: 8002073
• 负责人: BARBARA J MEYER
• 金额: $ 53.25万
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8002073
• 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. PUBLIC HEALTH RELEVANCE: A protein we found to be pivotal for sex determination in the round worm C. elegans is 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. In addition, we have discovered protein complexes with shared components that participate in many chromosome behaviors including chromosome-wide gene regulation through dosage compensation, mitotic chromosome segregation, and the control of meiotic chromosome recombination. Disruption of these proteins causes severe chromosome segregation defects and genomic instability. Examination of tumors invariably reveals the genome to be rearranged and aneuploid, showing the significant role chromosome instability plays in generating cancerous cells. Our protein complexes give us insight into the mechanisms underlying the genome rearrangements associated with such a cancerous state.

描述（由申请方提供）：剂量敏感性信号在发育过程中的细胞命运决定中发挥重要作用。我们研究的一个领域是研究分子信号中微小的数量差异转化为显着不同的发育命运的机制。我们的长期目标之一是剖析数量信号和基因开关，指定性的命运在线虫C。优美的C.线虫通过计算与倍性相关的X染色体数量来确定性别，常染色体组（X：一个信号）。我们发现，X染色体上的一组基因，称为X信号元件（XSEs），通过转录和前mRNA机制抑制性别决定开关基因xol-1的活性来传递X染色体剂量。另一组称为常染色体信号元件（ASE）的基因通过拮抗XSE激活xol-1来传递倍性。xol-1指定活跃时的雄性命运和非活跃时的雌雄同体命运。我们的工作是研究XSE和ASE相互拮抗以决定性别的分子机制。一种XSE是称为SEX-1的核激素受体（NHR），其是维甲酸受体（RAR）基因家族的同源物，其参与用于所有后生动物中的图案化和细胞分化的信号传导途径。RAR的破坏与人类癌症有关，这一知识导致类维生素A用于治疗白血病。从模式生物如C.线虫的NHRs功能的遗传途径将提供一个机会，发现其他基因靶点的药物治疗，这可能适用于人类。第二个长期目标是了解X染色体剂量补偿的机制，它使性别之间的X表达均衡。我们定义了一种蛋白复合物（DCC），它结合XX动物的两条X染色体，使X表达抑制一半。该复合体的成员还在有丝分裂和减数分裂染色体的压实、分解和分离以及同源减数分裂染色体之间的遗传重组的控制中发挥重要作用。蛋白质复合物不仅对基因的正常表达和生存力至关重要，而且大多数组分对基因组的稳定性至关重要。因此，研究剂量补偿将有助于我们理解染色体分离错误和减数分裂重组中断引起的基因组不稳定性。我们已经鉴定了靶向X染色体的顺式作用调节元件，以通过DCC进行抑制，并发现了DCC识别和结合X的基本原理。我们未来的工作将探索染色体结构，DCC结合，和染色体范围内的基因阻遏之间的联系。 公共卫生相关性：我们发现一种蛋白质是蛔虫性别决定的关键。线虫是视黄酸受体（RAR）基因家族的同源物，其参与用于所有后生动物中的图案化和细胞分化的信号传导途径。RAR的破坏与人类癌症有关，这一知识导致类维生素A用于治疗白血病。从模式生物如C.线虫的NHRs功能的遗传途径将提供一个机会，发现其他基因靶点的药物治疗，这可能适用于人类。此外，我们还发现了具有共同组分的蛋白质复合物，这些蛋白质复合物参与许多染色体行为，包括通过剂量补偿进行的全染色体基因调控、有丝分裂染色体分离以及减数分裂染色体重组的控制。这些蛋白质的破坏导致严重的染色体分离缺陷和基因组不稳定性。对肿瘤的检查总是揭示基因组重排和非整倍体，表明染色体不稳定性在产生癌细胞中起着重要作用。我们的蛋白质复合物使我们深入了解与这种癌症状态相关的基因组重排的机制。