Xia Brian, Gerstin Ed, Schones Dustin E, Huang Wendong, Steven de Belle J
Canyon Crest Academy, San Diego, CA 92130, USA.
Department of Diabetes Complications and Metabolism, City of Hope, Duarte, CA 91010, USA.
Aging (Albany NY). 2016 Nov 25;8(11):2988-3008. doi: 10.18632/aging.101107.
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.
早年营养对健康和发育的跨代影响最近受到了越来越多的关注。然而，跨代传递的潜在机制才刚刚开始显现，表观遗传学可能是最重要的机制。我们最近报道了首个用于研究早年饮食干预后长寿的跨代编程的动物模型，这使得能够通过研究来确定潜在的表观遗传机制。我们在此报告，羽化后用低蛋白（LP）饮食进行饮食干预（PDM）会上调E(z)（一种H3K27特异性甲基转移酶）的蛋白质水平，导致H3K27三甲基化（H3K27me3）水平升高。这种由PDM介导的H3K27me3变化与F0代果蝇及其F2代后代的寿命缩短相对应。在F0代亲本中，通过RNAi特异性介导羽化后敲低E(z)或用EPZ - 6438对其酶功能进行药理学抑制，可延长寿命，同时使各代的H3K27me3水平降低。重要的是，在LP饮食中添加EPZ - 6438可完全缓解LP PDM对寿命的缩短作用，这支持了依赖E(z)的H3K27me3水平升高是主要原因，以及早年时期是通过表观遗传调控来编程寿命的关键时期。这些观察结果确立了E(z)介导的H3K27me3是长寿营养编程的一种表观遗传机制，并支持使用EPZ - 6438来延长寿命。
