Function and regulation of the ETS transcriptional repressor Tel-1/Yan

描述（由申请人提供）：这项工作的长期目标是阐明如何转录！在保守信号网络下游运行的电路介导环境特异性发育反应。由于基因表达的精确协调调控是所有生物过程的基础，即使是轻微的失衡也可能导致严重的缺陷和疾病。我们的方法是利用遗传上易处理的果蝇系统，发现新的策略的基因调控，解剖它们在体内的分子机制的细节水平，然后确认它们的保护和哺乳动物系统的相关性。该提案的目的是研究保守的ETS家族转录抑制子的体内功能和调节，在果蝇中称为Yan，在人类中称为Tel 1。该提案描述了一种多方面的方法，结合体内遗传，分子，生物化学和基因组检测，以解决这一假设，即由Tel 1/Yan的SAM结构域介导的同型和异型相互作用允许与染色质的复杂关联，这对发育基因调控至关重要。具体的目的是测试的假设，严的自我关联的能力是需要其作为一个转录抑制因子在体内的功能，调查机制，从而调节严聚合允许它扩散到染色质侧翼的一个典型的高亲和力结合位点，并探讨这些监管策略的保护相对于人类Tel 1。这些实验的结果将定义一个新的模式，在转录抑制，其中动态聚合的基因特异性转录调节因子可以调节下游靶基因的表达，以响应不断变化的信号条件。 由于我们正在研究的信号分子在哺乳动物中具有保守的功能，并且由于Tel 1是白血病相关染色体重排的常见靶点，因此我们的发现将直接适用于了解人类发育和疾病。考虑到Tel 1自我关联的能力被认为是几种常见白血病恶性转化的驱动力，这些研究产生的机制发现将为未来开发新的治疗干预措施以治疗Tell相关癌症提供重要基础。

DESCRIPTION (provided by applicant): The long-term objectives of this work are to elucidate how transcriptiona! circuitries operating downstream of conserved signaling networks mediate context-specific developmental responses. Because precisely orchestrated regulation of gene expression is fundamental to all biological processes, even slight imbalances can lead to serious defects and diseases. Our approach is to exploit the genetically tractable Drosophila system to uncover novel strategies of gene regulation, to dissect them in vivo at a molecular mechanistic level of detail, and then to confirm their conservation and relevance to mammalian systems. The goal of this proposal is to investigate the in vivo function and regulation of a conserved ETS family transcriptional repressor, referred to as Yan in Drosophila and Tel1 in humans. The proposal describes a multifaceted approach combining in vivo genetic, molecular, biochemical and genomic assays to address the hypothesis that homo- and heterotypic interactions mediated by the SAM domain of Tel1/Yan permit a complex association with chromatin that is essential for developmental gene regulation. The specific aims are to test the hypothesis that the ability of Yan to self-associate is required for its function as a transcriptional repressor in vivo, to investigate the mechanisms whereby regulated Yan polymerization allows it to spread into chromatin flanking a canonical high affinity binding site, and to explore the conservation of these regulatory strategies with respect to human Tel1. The results of these experiments will define a novel paradigm in transcriptional repression, in which dynamic polymerization of a gene specific transcriptional regulator can modulate expression of downstream target genes in response to changing signaling conditions. Because the signaling molecules we are studying have conserved functions in mammals, and because Tel1 is a frequent target of leukemia-associated chromosomal rearrangements, our findings will be directly applicable to understanding human development and disease. Given that the ability of Tel1 to self-associate is thought to provide a driving force toward malignant transformation in several common leukemias, the mechanistic discoveries emanating from these studies will provide an important foundation for developing novel therapeutic interventions to treat Tell-associated cancers in the future.