Phenotypic cross-species conservation and cross-generation directionality switching in epigenetic inheritance

Evidence supporting non-DNA sequence-based inheritance in animals has increasingly been described in recent years, often under intergenerational inheritance or transgenerational epigenetic inheritance (TEI). Existence of the latter, a stronger indicator of germline transmission, has been demonstrated in invertebrates and mammals alike. The mechanisms and physiological implications of TEI, however, remain unclear. Here, in an unbiased approach, we compared existing transcriptomic data associated with so far available Drosophila models of inter- and trans-, and rodent models of inter-generational inheritance; observed phenotypic cross-species conservation and cross-generation directionality shift therein; and confirmed these observations experimentally in flies. Specifically, previous models of cold and diet-induced inheritance in both flies and mice were commonly associated with altered regulation of proteolysis genes. Besides, fly TEI models were in general characterized by opposite phenotypic regulation in transgenerational offsprings, compared to the ancestors. As insulin-producing cell (IPC) ablation was also associated with proteolysis gene dysregulation in one of the mouse models, we opted to use genetic ablation of IPCs in flies for the experimental validation. Remarkably, the ablation led to transcriptomic alterations across multiple generations, with dysregulated genes showing proteolysis enrichment. Similarly, phenotypic directionality changed in the opposite direction in transgenerational offsprings, in comparison of the ancestors. These results support evolutionary conservation, and both physiologically adaptive and maladaptive consequences of germline mediated epigenetic inheritance.