Non-genetic Transgenerational Inheritance of Acquired Traits in Drosophila

It is increasingly recognized that acquired traits may be transgenerationally transmitted through non-DNA sequence-based elements, with epigenetics as perhaps the most important mechanism. Here we review examples of non-genetic transgenerational inheritance in Drosophila , highlighting transgenerational programming of metabolic status and longevity, one particular histone modification as an evolutionarily conserved underlying mechanism, and important implications of such studies in understanding health and diseases. with a decrease in glycogen levels. Consistently, gene expression analyses demonstrated decreased expression of the genes involved in fat body lipolysis and gluconeogenesis, and increased expression of the ones involved in gut lipolysis, fatty acid synthesis, sugar transport and glycolysis. These results have confirmed the traditional models of insulin signaling, in which impaired insulin sensitivity leads to global increases in circulating blood sugars and decreases in sugar storage. Both glucose and trehalose levels were elevated, with TAG unaffected in the F2 male larvae; trehalose was elevated while TAG was decreased, with glucose unaffected in the F2 female larvae, supporting the existence of gender-dependent differences in transgenerational inheritance of metabolic programming. These results have demonstrated the long-lasting and transgenerational effects of early-life (post-eclosion) nutrition on metabolic status, establishing Drosophila as useful model to TEI of of metabolic homeostasis increase of E(z)-dependent H3K27me3 was seen in the F0 parents and their F2 offspring. Correspondingly, longevity was reduced in both F0 and F2 flies. These results suggest that early-life dietary insults may trigger E(z)-mediated H3K27me3 changes via misregulation of E(z), and consequently nutrition-induced H3K27me3 dysfunction may be transmitted across generations and underlie TEI of nutritional programming of longevity. First, E(z)-mediated H3K27me3 was found to be necessary for TEI of longevity programming, as early-life RNAi-mediated specific knockdown of E(z) only in the F0 parents extended longevity while reduc ing H3K27me3 activity, and early-life specific inhibition of E(z) enzymatic function with EPZ-6438 (a highly EZH2-selective inhibitor) also extended lifespan while rendering the H3K27me3 level low across generations. Importantly, the effects of RNAi-mediated knock down on H3K27me3 and longevity were specific, as (I) similar effects were observed with two independent RNAi transgenes, (II) the E(z) protein level was normal in the F2 generation after its knockdown in the F0 parents, and (III) longevity, E(z), and H3K27me3 levels were not affected without heat shock to induce RNAi transgenes. Similarly, the EPZ-6438-induced effects were specific, as (I) EPZ-6438, as a phase II clinical drug, is highly EZH2 selective and considered safe [142 ], and (II) E(z) protein was unaffected by EPZ-6438 even in the F0 parents. In addition, H3K27me3 was found to be sufficient for TEI of longevity programming, as EPZ-6438 greatly alleviated the longevity-reducing effect of the LP diet, while counterbalancing its upregulation of H3K27me3 across the F0 to F2 generations. Our data have convincingly demonstrated that E(z)-mediated H3K27me3 activity may play a critical role in the general health of an organism and function as one epigenetic