Hibernation is employed by animals to withstand periods of low energy supply associated with cold temperatures. When adapted to cold, C. elegans can survive near-freezing temperatures for several days. Among factors promoting C. elegans cold survival is the conserved ribonuclease REGE-1/Regnase-1. The main target of REGE-1 is mRNA encoding a transcription factor, ETS-4, previously implicated in insulin signaling and the regulation of body fat. We found that the abnormal accumulation of ETS-4 is also responsible for the reduced cold resistance of
rege-1 mutants. Conversely,
ets-4 mutants survive cold much better than wild type. Through genetics and functional genomics, we found that, in the cold, the loss of ETS-4 leads to the activation of two transcription factors, DAF-16/FOXO and PQM-1. In contrast to standard cultivation temperatures, where these transcription factors play antagonistic functions, our analysis suggests that, in the cold, these transcription factors cooperate to induce transcription of specific genes. We show that one of their targets, FTN-1/ferritin, facilitates cold survival, and propose that it does so by detoxifying harmful iron species.