Transcriptional regulation of Caenorhabditis elegans FOXO/DAF-16 modulates lifespan.
Transcriptional regulation of Caenorhabditis elegans FOXO/DAF-16 modulates lifespan.
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DOI：
10.1186/2046-2395-3-5
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
Tissenbaum HA
中科院分区：
文献类型：
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作者：
Bansal A;Kwon ES;Conte D Jr;Liu H;Gilchrist MJ;MacNeil LT;Tissenbaum HA
胰岛素/IGF-1信号传导在整个生育期的长寿中起着核心作用。In C.在线虫中，叉头框O（FOXO）转录因子，β-16是胰岛素/IGF-1信号传导的主要靶标，β-16的多种同种型（a、B和d/f）调节寿命、代谢、dauer形成和应激抗性。到目前为止，哺乳动物FOXO和FOXO-16的整个发育调控都集中在翻译后调控上，而很少关注转录调控。In C. elegans，我们以前已经表明，β-16 d/f与β-16 a合作，以促进长寿。在这项研究中，我们产生的转基因株表达近内源性水平的daf-16 a或daf-16 d/f，并检查时间表达的亚型，以进一步确定这些亚型如何有助于寿命调节。在这里，我们表明，β-16 a是敏感的基因剂量的变化和胰岛素/IGF-1信号水平的改变。有趣的是，我们发现，随着蠕虫年龄的增长，肠道表达的daf-16 d/f，而不是daf-16 a的转录水平显着上调。阻止这种转录上调会缩短寿命，这表明daf-16 d/f的转录调节促进寿命。在转录调节因子的RNAi筛选中，我们鉴定了elt-2（加塔转录因子）和swsn-1（SWI/SNF复合物的核心亚基）作为daf-16 d/f基因表达的关键调节因子。ELT-2和另一个加塔因子ELT-4通过β-16 a和β-16 d/f促进长寿，而SWI/SNF复合物的组分特异性地通过β-16 d/f促进长寿。我们的研究结果表明，C。FOXO/daf-16是一个重要的调控事件。考虑到FOXO在物种间的保护，我们的研究结果确定了一个新的FOXO调节层，作为哺乳动物寿命和年龄相关疾病（如癌症和糖尿病）的潜在决定因素。
Insulin/IGF-1 signaling plays a central role in longevity across phylogeny. In C. elegans, the forkhead box O (FOXO) transcription factor, DAF-16, is the primary target of insulin/IGF-1 signaling, and multiple isoforms of DAF-16 (a, b, and d/f) modulate lifespan, metabolism, dauer formation, and stress resistance. Thus far, across phylogeny modulation of mammalian FOXOs and DAF-16 have focused on post-translational regulation with little focus on transcriptional regulation. In C. elegans, we have previously shown that DAF-16d/f cooperates with DAF-16a to promote longevity. In this study, we generated transgenic strains expressing near-endogenous levels of either daf-16a or daf-16d/f, and examined temporal expression of the isoforms to further define how these isoforms contribute to lifespan regulation. Here, we show that DAF-16a is sensitive both to changes in gene dosage and to alterations in the level of insulin/IGF-1 signaling. Interestingly, we find that as worms age, the intestinal expression of daf-16d/f but not daf-16a is dramatically upregulated at the level of transcription. Preventing this transcriptional upregulation shortens lifespan, indicating that transcriptional regulation of daf-16d/f promotes longevity. In an RNAi screen of transcriptional regulators, we identify elt-2 (GATA transcription factor) and swsn-1 (core subunit of SWI/SNF complex) as key modulators of daf-16d/f gene expression. ELT-2 and another GATA factor, ELT-4, promote longevity via both DAF-16a and DAF-16d/f while the components of SWI/SNF complex promote longevity specifically via DAF-16d/f. Our findings indicate that transcriptional control of C. elegans FOXO/daf-16 is an essential regulatory event. Considering the conservation of FOXO across species, our findings identify a new layer of FOXO regulation as a potential determinant of mammalian longevity and age-related diseases such as cancer and diabetes.