DAF-12 germline-to-soma signaling mediates transgenerational longevity in C. elegans

Development requires the complex coordination of gene regulatory networks that must remain robust in the face of variable environmental cues. In Caenorhabditis elegans, the nuclear hormone receptor DAF-12 integrates metabolic cues and hormonal signals to control important life history decisions, including development, reproduction, and the rate of aging. Here, we tested the involvement of DAF-12 germline-to-soma signaling in two transgenerational longevity mutants, wdr-5 and jhdm-1. We have previously shown that both mutant populations gradually accumulate repressive H3K9me2 over multiple generations, which is necessary and sufficient for their lifespan extension. We find that daf-12 activity was required for the epigenetic establishment of longevity in both mutant populations, but was only necessary for maintaining longevity in a wdr-5 mutant background. Because DAF-12 also functions as a key regulator of dauer diapause, an alternative developmental stage triggered by environmental stress, we also tested the genetic relationship at earlier points in development. Surprisingly, mutations in either wdr-5 or jhdm-1 rescued the dauer defect of daf-12 mutants, and we found a synergistic effect on unchallenged larval development in wdr-5; daf-12 double mutants. These differing epistatic relationships indicate that, although the acquisition of longevity in both wdr-5 and jhdm-1 mutant populations shares a common mechanism, the impacts on somatic phenotypes (including lifespan extension) proceed via distinct pathways. Together, these results show how heritable chromatin states can co-opt existing developmental programs to influence key developmental decisions.