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

描述（由申请人提供）：DAF-16/FOXO家族转录因子是进化上保守的主调控因子，能够整合各种环境刺激并协调发育、代谢、应激反应和寿命。众所周知，人类FOXO蛋白的失调在癌症和糖尿病等与年龄相关的疾病中起着关键作用。为了使DAF-16/ foxo发挥其多面性和核心作用，它们的转录活动需要得到精确的调控；然而，DAF-16/ foxo介导的基因转录调控机制在很大程度上是未知的。本研究的长期目标是全面阐明DAF-16/FOXO转录活性如何在细胞核中受到调控，以及这种调控如何影响寿命的决定。我们最近发现，秀丽隐杆线虫核蛋白宿主细胞因子1 （HCF-1）的同源物通过抑制DAF-16介导的基因调控，作为DAF-16的辅助因子来调节寿命。由于HCF-1是在秀丽隐杆线虫中报道的第一个DAF-16阴性辅助因子，这一发现为进一步研究DAF-16转录活性如何被调控提供了一个重要的入口。在Aim 1中，我们提出验证这样一个假设，即DAF-16介导的转录输出的特异性是由HCF-1和其他DAF-16辅助因子之间的相互作用决定的。在Aim 2中，我们提出验证HCF-1与SIR-2.1形成调控网络以调控DAF-16在特定靶基因上的转录活性的假设。在Aim 3中，我们建议确定调节daf -16介导的基因转录的其他转录和染色质因子。由于DAF-16及其辅助因子（HCF-1, SIR-2.1, SMK-1, BAR-1, CTBP-1）都是高度保守的，我们的研究结果将为FOXO调控和哺乳动物寿命决定提供重要的见解。此外，已知DAF-16的哺乳动物同源基因及其辅助因子在许多人类疾病（如癌症和糖尿病）的发病机制中发挥关键作用，我们的研究结果可能会启发未来的治疗开发，旨在缓解人类中一些与年龄相关的病理。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Transcription factors of the DAF-16/FOXO family are highly conserved master regulators capable of integrating diverse environmental stimuli and coordinating development, metabolism, stress responses, and longevity. This application proposes to use the powerful genetic model C. elegans to investigate how several highly conserved DAF-16 co-factors function together to precisely control DAF-16-mediated gene regulation. The findings from this proposal will have direct relevance to FOXO regulation in mammals and will provide important insights into the biology of aging, and may inspire future therapeutic development that aims to benefit longevity and alleviate age-related diseases.