ETS-4 Is a Transcriptional Regulator of Life Span in Caenorhabditis elegans

Abstract

Aging is a complex phenotype responsive to a plethora of environmental inputs; yet only a limited number of transcriptional regulators are known to influence life span. How the downstream expression programs mediated by these factors (or others) are coordinated into common or distinct set of aging effectors is an addressable question in model organisms, such as C. elegans. Here, we establish the transcription factor ETS-4, an ortholog of vertebrate SPDEF, as a longevity determinant. Adult worms with ets-4 mutations had a significant extension of mean life span. Restoring ETS-4 activity in the intestine, but not neurons, of ets-4 mutant worms rescued life span to wild-type levels. Using RNAi, we demonstrated that ets-4 is required post-developmentally to regulate adult life span; thus uncoupling the role of ETS-4 in aging from potential functions in worm intestinal development. Seventy ETS-4-regulated genes, identified by gene expression profiling of two distinct ets-4 alleles and analyzed by bioinformatics, were enriched for known longevity effectors that function in lipid transport, lipid metabolism, and innate immunity. Putative target genes were enriched for ones that change expression during normal aging, the majority of which are controlled by the GATA factors. Also, some ETS-4-regulated genes function downstream of the FOXO factor, DAF-16 and the insulin/IGF-1 signaling pathway. However, epistasis and phenotypic analyses indicate that ets-4 functioned in parallel to the insulin/IGF-1 receptor, daf-2 and akt-1/2 kinases. Furthermore, ets-4 required daf-16 to modulate aging, suggesting overlap in function at the level of common targets that affect life span. In conclusion, ETS-4 is a new transcriptional regulator of aging, which shares transcriptional targets with GATA and FOXO factors, suggesting that overlapping pathways direct common sets of lifespan-related genes.

Efficient generation of transgenic reporter strains and analysis of expression patterns in Caenorhabditis elegans using library MosSCI

“…ETS-4 is a transcription factor that regulates aging (Thyagarajan et al, 2010). CUL-4 is a cullin ubiquitin ligase that prevents re-replication of DNA (Zhong et al, 2003).…”

Neuronal Inputs and Outputs of Aging and Longevity

“…The distinct functional roles of pleiotropic genes during development versus aging are also demonstrated by the uncoupling of their gene functions between these two processes (Chen et al, 2007; Shen et al, 2009; Thyagarajan et al, 2010). In some cases, strong loss-of-function (or null) mutations have been found to affect embryonic development in C. elegans , whereas weaker mutant alleles of the same gene have been shown to affect adult lifespan (Kenyon et al, 1993; Kimura et al, 1997; Gems et al, 1998; Boehm and Slack, 2005), suggesting that essential developmental genes can have deleterious effects late in life.…”

Differentiation of Carbon Dioxide-Sensing Neurons in Caenorhabditis elegans Requires the ETS-5 Transcription Factor

“…The binding sites for mammalian ETS proteins are well characterized, and at least some of the C. elegans ETS proteins bind to cis-regulatory motifs that are similar to mammalian ETS binding sites (Wagmaister et al 2006;Flames and Hobert 2009;Thyagarajan et al 2010). All mammalian ETS family members bind to the conserved core recognition sequence 59-GGA(A/T)-39, and the bases surrounding this core recognition sequence determine binding specificity for individual ETS proteins (Macleod et al 1992;Hollenhorst et al 2011).…”

“…By contrast, the ets-4 and lin-1 genes are not known to affect neuronal differentiation. ETS-4 is a transcriptional regulator of life span and ets-4 mutants have significantly extended life spans relative to wild-type animals (Thyagarajan et al 2010). LIN-1 acts in the MAP kinase pathway to control vulval development (Sternberg 2005) and some lin-1 mutants have a multivulva or an egg-laying defective phenotype (Jacobs et al Figure 4 Gene expression is reduced in the BAG neurons of ets-5 mutants.…”