Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Lewis-Sigler Institute for Integrative Genomics and Dept. of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Cell. 2013 Aug 1;154(3):676-690. doi: 10.1016/j.cell.2013.07.006.
Reduced insulin/IGF-1-like signaling (IIS) extends C. elegans lifespan by upregulating stress response (class I) and downregulating other (class II) genes through a mechanism that depends on the conserved transcription factor DAF-16/FOXO. By integrating genome-wide mRNA expression responsiveness to DAF-16 with genome-wide in vivo binding data for a compendium of transcription factors, we discovered that PQM-1 is the elusive transcriptional activator that directly controls development (class II) genes by binding to the DAF-16-associated element (DAE). DAF-16 directly regulates class I genes only, through the DAF-16-binding element (DBE). Loss of PQM-1 suppresses daf-2 longevity and further slows development. Surprisingly, the nuclear localization of PQM-1 and DAF-16 is controlled by IIS in opposite ways and was also found to be mutually antagonistic. We observe progressive loss of nuclear PQM-1 with age, explaining declining expression of PQM-1 targets. Together, our data suggest an elegant mechanism for balancing stress response and development.
胰岛素/胰岛素样生长因子-1 信号通路（IIS）的减少通过上调应激反应（I 类）和下调其他（II 类）基因来延长秀丽隐杆线虫的寿命，其机制依赖于保守的转录因子 DAF-16/FOXO。通过将 DAF-16 对全基因组 mRNA 表达的响应与转录因子综合组的全基因组体内结合数据进行整合，我们发现 PQM-1 是一个难以捉摸的转录激活因子，它通过与 DAF-16 相关元件（DAE）结合来直接控制发育（II 类）基因。DAF-16 仅通过 DAF-16 结合元件（DBE）直接调节 I 类基因。PQM-1 的缺失抑制了 daf-2 的长寿，并进一步减缓了发育。令人惊讶的是，IIS 以相反的方式控制 PQM-1 和 DAF-16 的核定位，并且还发现它们是相互拮抗的。我们观察到随着年龄的增长，核 PQM-1 逐渐丢失，这解释了 PQM-1 靶基因表达的下降。总的来说，我们的数据表明了一种平衡应激反应和发育的优雅机制。
