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

描述（由申请人提供）：转录因子β-16/FOXO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蛋白的失调在与年龄相关的疾病如癌症和糖尿病中起关键作用。为了使β-16/FOXO发挥其多方面的核心作用，其转录活性需要被精细地调控;然而，β-16/FOXO介导的基因转录调控的潜在机制在很大程度上是未知的。该提案的长期目标是全面阐明在细胞核中如何调节α-16/FOXO转录活性以及这种调节如何有助于寿命决定。我们最近发现C.线虫的核蛋白宿主细胞因子1（HCF-1）的直系同源物通过作为抑制β-16介导的基因调控的β-16辅因子发挥作用来调节寿命。由于HCF-1是C.这一发现为进一步研究β-16转录活性是如何被调控的提供了一个重要的切入点。在目的1中，我们提出了测试的假设，即HCF-1和其他的HCF-16辅因子之间的相互作用决定的特异性的HCF-16介导的转录输出。在目的2中，我们提出了一个假设，即HCF-1与SIR-2.1形成一个调控网络，以调节特定靶基因上的转录活性。在目标3中，我们提出了确定额外的转录和染色质因子，调节β-16介导的基因转录。由于FOXO-16及其辅因子（HCF-1、SIR-2.1、SMK-1、BAR-1、CTBP-1）都是高度保守的，因此我们的研究结果将为FOXO在哺乳动物中的调节和寿命决定提供重要的见解。此外，已知哺乳动物的β-16及其辅因子在许多人类疾病的发病机制中起关键作用，例如癌症和糖尿病，我们的研究结果可能会激发未来的治疗开发，旨在减轻人类中的一些年龄相关的病理。 公共卫生相关性：转录因子β-16/FOXO家族是高度保守的主调节因子，能够整合不同的环境刺激并协调发育、代谢、应激反应和寿命。本申请建议使用功能强大的遗传模型C。elegans研究几种高度保守的β-16辅因子如何共同作用以精确控制β-16介导的基因调控。该提案的发现将与哺乳动物中的FOXO调节直接相关，并将为衰老生物学提供重要见解，并可能激发未来的治疗开发，旨在延长寿命和减轻与年龄相关的疾病。

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.