DAF-16 and PQM-1: Partners in longevity

years ago it was discovered that loss of insulin/IGF-1-like signaling (IIS) – such as occurs in daf-2(mutants ts – dramatically extends longevity in the nematode C. elegans via the FOXO transcription factor DAF-16 [1-3]. Under favorable conditions, DAF-16 remains cytosolic and transcriptionally inactive[2-4]; under stress, it is driven into the nucleus, leading to both up-regulation and down-regulation of large sets of genes, referred to as Class I and II, respectively [5]. Identifying these genes and their functions is key to understanding the molecular and biochemical determinants of aging and longevity. While several studies have been performed to determine the genes regulated by DAF-16, agreement on the identity of targets has been limited to a relatively small number of top responders [6]. Moreover, recent results have made it clear that while DAF-16 is responsible for the activation of Class I genes through the DAF-16 binding element (DBE), it does not interact directly with the upstream promoter regions of Class II genes, leaving the down-regulation of the latter in IIS mutants unexplained [7, 8]. To address these issues, we first performed a careful meta-analysis of all available genomewide expression profiles with DAF-16 active (nuclear) vs. inactive (cytosolic or null) [8]. We reprocessed relevant raw data from various laboratories, and used a voting algorithm developed specifically for this purpose to construct a consensus ranking of all C. elegans genes in terms of their responsiveness to DAF-16. This allowed us to redefine Class I and Class II targets with unprecedented sensitivity and specificity. Next, using a combination of computational and experimental methods, we discovered that the little-studied transcription factor PQM-1 regulates Class II genes (and Class I to a lesser extent), via the DAF-16 associated element (DAE), a GATA-containing motif previously lacking an identified binding factor [5]. Integrating our DAF-16 target ranking with ChIP-Seq data from the modENCODE project [9] showed that PQM-1 binding is strongly associated with both proximal upstream DAE occurrence and responsiveness to DAF-16. Indeed, a reporter gene assay confirmed that PQM-1 activates transcription in a DAE-dependent manner. Editorial Next, we investigated whether and how PQM-1 subcellular localization depends on IIS status. Using GFP translational fusions, we found that the nuclear presence of PQM-1 and DAF-16 is controlled by IIS in opposite ways. A model emerged in which both the DBE and the DAE contribute to the expression of Class I genes, while Class II genes are exclusively controlled through the …