Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila

Abstract

Transgenerational effects on health and development of early-life nutrition have gained increased attention recently. However, the underlying mechanisms of transgenerational transmission are only starting to emerge, with epigenetics as perhaps the most important mechanism. We recently reported the first animal model to study transgenerational programming of longevity after early-life dietary manipulations, enabling investigations to identify underlying epigenetic mechanisms. We report here that post-eclosion dietary manipulation (PDM) with a low-protein (LP) diet upregulates the protein level of E(z), an H3K27 specific methyltransferase, leading to higher levels of H3K27 trimethylation (H3K27me3). This PDM-mediated change in H3K27me3 corresponded with a shortened longevity of F0 flies as well as their F2 offspring. Specific RNAi-mediated post-eclosion knockdown of E(z) or pharmacological inhibition of its enzymatic function with EPZ-6438 in the F0 parents improved longevity while rendering H3K27me3 low across generations. Importantly, addition of EPZ-6438 to the LP diet fully alleviated the longevity-reducing effect of the LP PDM, supporting the increased level of E(z)-dependent H3K27me3 as the primary cause and immediate early-life period as the critical time to program longevity through epigenetic regulation. These observations establish E(z)-mediated H3K27me3 as one epigenetic mechanism underlying nutritional programming of longevity and support the use of EPZ-6438 to extend lifespan.

A ‘phenotypic hangover’ – the predictive adaptive response and multigenerational effects of altered nutrition on the transcriptome of Drosophila melanogaster

“…For example, a low protein diet given to Drosophila can increase H3K27me3 through upregulation of the E(z) protein. Interestingly, while the upregulation of the (E)z protein was not detected in the F2 generation, the associated increase in methylation H3K27me3 was in fact detected in the F2 generation (Xia et al, 2016) and the coordinated effect on longevity was also present through to the F2 generation. This suggests that while the gene expression and protein level is not inherited per se, the effects and/or functions of those genes possibly could be.…”

“…Thus traits present in the F2 generation should be considered as multigenerational, rather than transgenerational, as they could have been induced by direct environmental exposure through the fetus and the germ line. To reflect this, some studies searching for evidence of true transgenerational inheritance are declining to assay the F1 generation entirely (Xia et al, 2016) due to the fact that transmission to the F1 generation can be indicative of both parental effects and programming (Xia and de Belle, 2016). Thus, here we describe our findings from the F1 and F2 generations as multigenerational inheritance, since the gene expression changes induced by the environment in the parental generation revert to F0 levels after the F2 generation.…”

Sir2 is essential for intergenerational effects of parental diet on offspring metabolism in Drosophila

“…Previous studies have suggested that the nutrient-induced intergenerational effects are transmitted to offspring by H3K9/K27me3 in germline cells (Guida et al, 2019;Öst et al, 2014;Xia et al, 2016). Recently, it has been reported that maternal H3K9me3 is directly inherited to next generation and required for normal embryogenesis in mice and Drosophila (Inoue et al, 2017a;Inoue et al, 2017;Zenk et al, 2017).…”

“…Early-life low-protein diet induced a higher level of H3 Lys27 trimethylation (H3K27me3) by upregulation of the protein level of E(z), H3K27 specific methyltransferase. This altered H3K27me3 was associated with a short lifespan in the offspring (Xia et al, 2016). Two days of high/low-sugar diet elicited obesity in offspring, which involves H3K9/K27me3-dependent reprogramming of metabolic genes (Öst et al, 2014).…”

Non-genetic Transgenerational Inheritance of Acquired Traits in Drosophila

“…Finally, tissue-specific and time-dependent genetic manipulations may be readily achievable for most genes, for instance, using the 22,270 transgenic lines (currently, covering ~88% of all predicted protein-coding genes) from the Vienna Drosophila Resource Center [73]. Therefore, Drosophila is well-suited for both correlational and mechanistic studies focusing on transgenerational programming of longevity after nutritional or environmental manipulations in the F0 parents [74][75][76][77].…”