Analysis of Nematode Sex Determination

线虫性别测定分析

• 批准号: 8197652
• 负责人: BARBARA J MEYER
• 金额: $ 53.43万
• 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/8197652
• 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(由申请人提供)：剂量敏感信号在发育过程中对细胞命运的决定起着至关重要的作用。我们研究的一个领域是研究分子信号的微小数量差异转化为截然不同的发育命运的机制。我们的长期目标之一是剖析线虫的数量信号和基因开关，这些开关决定了线虫的性别命运。线虫通过计算X染色体相对于倍性的数目来决定性别，常染色体组(X：一种信号)。我们发现，X上的一组基因，称为X信号元件(XSE)，通过转录和前mRNA机制抑制性别决定开关基因Xol-1的活性，从而传递X染色体的剂量。另一组被称为常染色体信号元件(ASE)的基因通过对抗XSE来激活Xol-1来传递倍性。Xol-1指定活动时的雄性命运和不活动时的两性命运。我们的工作研究了XSE和ASES相互对抗以决定性别的分子机制。一种XSE是一种核激素受体(NHR)，称为性别-1，是维甲酸受体(RAR)基因家族的同源基因，参与所有后生动物中用于模式形成和细胞分化的信号通路。RARs的中断与人类癌症有关，这一知识导致了维甲酸在白血病治疗中的使用。从秀丽线虫等模式生物中获得的关于NHR功能的遗传途径的信息将为发现其他药物治疗的基因靶点提供机会，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X在性别之间的表达相等。我们定义了一个蛋白质复合体(DCC)，它结合XX动物的两条X染色体，将X的表达抑制一半。该复合体的成员还在有丝分裂和减数分裂染色体的紧凑、分离和分离以及同源减数分裂染色体之间的遗传重组控制中发挥重要作用。蛋白质复合体不仅对适当的基因表达和活性是必不可少的，而且大多数成分对基因组的稳定性也是必不可少的。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所导致的基因组不稳定性。我们已经发现了针对DCC抑制X染色体的顺式作用调控元件，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结合和染色体范围基因抑制之间的联系。 公共卫生相关性：我们发现在圆虫线虫中对性别决定至关重要的一种蛋白质是维甲酸受体(RAR)基因家族的同源基因，该基因家族参与了所有后生动物中用于模式形成和细胞分化的信号通路。RARs的中断与人类癌症有关，这一知识导致了维甲酸在白血病治疗中的使用。从秀丽线虫等模式生物中获得的关于NHR功能的遗传途径的信息将为发现其他药物治疗的基因靶点提供机会，这可能适用于人类。此外，我们还发现了具有共同组成的蛋白质复合体，它们参与了许多染色体行为，包括通过剂量补偿、有丝分裂染色体分离和控制减数分裂染色体重组来调节染色体范围的基因。这些蛋白质的破坏会导致严重的染色体分离缺陷和基因组不稳定。对肿瘤的检查总是揭示出基因组要重排和非整倍体，这表明染色体不稳定在产生癌细胞方面起着重要作用。我们的蛋白质复合体让我们深入了解与这种癌症状态相关的基因组重排的潜在机制。