A genetic program mediates cold-warming response and promotes stress-induced phenoptosis in C. elegans

Abstract

How multicellular organisms respond to and are impacted by severe hypothermic stress is largely unknown. From C. elegans screens for mutants abnormally responding to cold-warming stimuli, we identify a molecular genetic pathway comprising ISY-1, a conserved uncharacterized protein, and ZIP-10, a bZIP-type transcription factor. ISY-1 gatekeeps the ZIP-10 transcriptional program by regulating the microRNA mir-60. Downstream of ISY-1 and mir-60, zip-10 levels rapidly and specifically increase upon transient cold-warming exposure. Prolonged zip-10 up-regulation induces several protease-encoding genes and promotes stress-induced organismic death, or phenoptosis, of C. elegans. zip-10 deficiency confers enhanced resistance to prolonged cold-warming stress, more prominently in adults than larvae. We conclude that the ZIP-10 genetic program mediates cold-warming response and may have evolved to promote wild-population kin selection under resource-limiting and thermal stress conditions.

Cold survival and its molecular mechanisms in a locally adapted nematode population

“…In these data, a pattern of declining RNA levels predominated in both AF16 and HK104, with 2584 genes expressed at lower levels upon cold treatment in both strains (at a false discovery rate of 0.15; Figure 3b). Functional-genomic analyses of the latter revealed enrichment for a variety of gene groups involved in growth and cellular metabolism (Figure 3d), as expected if cold-treated animals of both strains slow or arrest many biological processes (Jiang et al, 2018; Robinson & Powell, 2016). By contrast, relatively few genes in each strain were expressed at higher levels in the cold relative to an untreated control (Figure 3b).…”

“…Ultimately, as a complete picture of the biology of cold resistance becomes clear, it will likely integrate mechanisms operating in the two phases; and the failures in tropical C. briggsae could prove to manifest in either one. The transcription factor gene ZIP-10 , known to promote death during recovery after cold treatment (Jiang et al, 2018), was expressed less in tropical AF16 than in temperate HK104 in our profiles (Supplementary Table 1), suggesting that the trait divergence between the strains hinges on a mechanism distinct from the ZIP-10 pathway.…”

“…Our evolutionary analysis of wild worms complements an extensive literature on the basic biology of hypothermia response in laboratory C. elegans. An important thread of this prior work has highlighted the dieoff of animals re-introduced into warm temperatures after cold shock, and its physiological and transcriptomic correlates (Jiang et al, 2018; Robinson & Powell, 2016). For our expression profiling, instead of the re-warming recovery phase, we focused on the end of the cold exposure regimen, and the genes with high RNA levels at this timepoint.…”

“…That said, among the many other known molecular mechanisms of cold resistance in C. elegans (Jiang et al, 2018; Ma et al, 2015; Murray, Hayward, Govan, Gracey, & Cossins, 2007; Okahata, Wei, Ohta, & Kuhara, 2019; Robinson & Powell, 2016; Sonoda, Ohta, Maruo, Ujisawa, & Kuhara, 2016; Takagaki et al, 2020; Ujisawa et al, 2018), some are echoed in the genes we have validated in the trait. For instance, regulating membrane lipid composition and fluidity is well-characterized as a strategy for cold tolerance in the worm (Ma et al, 2015; Murray et al, 2007); the cholesterol processing gene ncr-1, which we found to be required for cold tolerance in C. elegans , is likely to act through this mechanism.…”

“…Cold tolerance assays were performed as described (Jiang et al, 2018). For a given biological replicate of a given strain or treatment condition, 20-30 worms were dispersed on each of 2-3 plates and raised at 20°C until 24 hours after they reached the L4 stage.…”