Investigate the Transcriptional Co-factors of DAF-16/FOXO in C. elegans

项目摘要： 转录因子家族是进化上保守的主调节因子 能够整合不同的环境刺激，协调发展，新陈代谢，压力 反应和寿命。众所周知，人类FOXO蛋白的失调在年龄增长中起着关键作用。 相关疾病，如癌症和糖尿病。为了实现其多方面的， 核心作用，它们的转录活动需要精心调控;然而， 潜在的调节β-16/FOXO介导的基因转录在很大程度上是未知的。长期 该提案的目标是全面阐明β-16/FOXO转录活性是如何被 在细胞核中的调节，以及这种调节如何有助于寿命的确定。我们最近 发现C.线虫核蛋白宿主细胞因子1（HCF-1）的直系同源物调节寿命 通过作为抑制β-16介导的基因调控的β-16辅助因子发挥作用。由于HCF-1是第一个 在C.这一发现提供了一个重要的切入点， 研究β-16转录活性是如何调节的。在目标1中，我们建议测试 这一假说认为，β-16介导的转录输出的特异性是由相互作用决定的， HCF-1和其他β-16辅因子之间的关系。在目标2中，我们提出测试HCF-1形成的假设， 具有SIR-2.1的调控网络，以调节特定靶基因上的STAT-16转录活性。在Aim中 3、我们提出了鉴定调节β-16介导的基因的其他转录和染色质因子， 转录。由于HCF-16及其辅因子（HCF-1、SIR-2.1、SMK-1、BAR-1、CTBP-1）都是高表达的， 我们的研究结果将为FOXO调控和长寿提供重要的见解 哺乳动物的决定此外，已知哺乳动物中的β-16及其辅因子的直向同源物， 在癌症和糖尿病等多种人类疾病的发病机制中起着关键作用， 我们的研究可能会激发未来的治疗发展，旨在减轻一些与年龄有关的 人类的病理学

Project Summary: Transcription factors of the DAF-16/FOXO family are evolutionarily conserved master regulators capable of integrating diverse environmental stimuli and coordinating development, metabolism, stress responses, and longevity. Deregulation of FOXO proteins in humans is well known to play a key role in age- related diseases such as cancer and diabetes. For DAF-16/FOXOs to achieve their multi-faceted and central roles, their transcriptional activities need to be exquisitely regulated; however, the mechanisms underlying the regulation of DAF-16/FOXO-mediated gene transcription are largely unknown. The long-term goal of this proposal is to elucidate comprehensively how DAF-16/FOXO transcriptional activities are regulated in the nucleus and how this regulation contributes to longevity determination. We recently discovered that the C. elegans ortholog of the nuclear protein host cell factor 1 (HCF-1) modulates longevity by functioning as a DAF-16 co-factor that inhibits DAF-16-mediated gene regulation. Since HCF-1 is the first DAF-16 negative co-factor reported in C. elegans, this finding provides an important entry point for further investigation of how DAF-16 transcriptional activities are regulated. In Aim 1, we propose to test the hypothesis that the specificity of DAF-16-mediated transcriptional output is determined by the interplay between HCF-1 and other DAF-16 co-factors. In Aim 2, we propose to test the hypothesis that HCF-1 forms a regulatory network with SIR-2.1 to regulate DAF-16 transcriptional activity on specific target genes. In Aim 3, we propose to identify additional transcription and chromatin factors that regulate DAF-16-mediated gene transcription. Since DAF-16 and its co-factors (HCF-1, SIR-2.1, SMK-1, BAR-1, CTBP-1) are all highly conserved, findings from our studies will provide important insights into FOXO regulation and longevity determination in mammals. Moreover, the mammalian orthologs of DAF-16 and its co-factors are known to play key roles in the pathogenesis of a number of human diseases, such as cancer and diabetes, findings from our studies may inspire future therapeutic development aiming to alleviate some of these age-related pathologies in humans.