Metabolism feeds into the regulation of epigenetics via metabolic enzymes and metabolites. However, metabolic features, and their impact on epigenetic remodeling during mammalian pre-implantation development, remain poorly understood. In this study, we established the metabolic landscape of mouse pre-implantation embryos from zygote to blastocyst, and quantified some absolute carbohydrate metabolites. We integrated these data with transcriptomic and proteomic data, and discovered the metabolic characteristics of the development process, including the activation of methionine cycle from 8-cell embryo to blastocyst, high glutaminolysis metabolism at blastocyst stage, enhanced TCA cycle activity from the 8-cell embryo stage, and active glycolysis in the blastocyst. We further demonstrated that oxidized nicotinamide adenine dinucleotide (NAD⁺) synthesis is indispensable for mouse pre-implantation development. Mechanistically, in part, NAD⁺ is required for the exit of minor zygotic gene activation (ZGA) by cooperating with SIRT1 to remove zygotic H3K27ac. In human, NAD⁺ supplement can promote the removal of zygotic H3K27ac and benefit pre-implantation development. Our findings demonstrate that precise and timely regulation of minor ZGA is controlled by metabolic dynamics, and enhance our understanding of the metabolism of mammalian early embryos.

代谢通过代谢酶和代谢物进入表观遗传学的调节。然而，在哺乳动物植入前发育过程中，代谢特征及其对表观遗传重塑的影响仍然知之甚少。在这项研究中，我们建立了小鼠植入前胚胎从受精卵到囊胚的代谢景观，并量化了一些绝对碳水化合物代谢物。我们将这些数据与转录组学和蛋白质组学数据相结合，发现了发育过程的代谢特征，包括从 8 细胞胚胎到胚泡的蛋氨酸循环的激活、胚泡阶段的高谷氨酰胺分解代谢、8 细胞的 TCA 循环活性增强胚阶段，以及囊胚中的活跃糖酵解。我们进一步证明了氧化的烟酰胺腺嘌呤二核苷酸（NAD⁺ ) 合成对于小鼠植入前发育是必不可少的。从机制上讲，NAD ⁺是通过与 SIRT1 合作去除合子 H3K27ac 来退出次要合子基因激活 (ZGA) 所必需的。在人体中，NAD ⁺补充剂可以促进合子 H3K27ac 的去除，有利于胚胎植入前的发育。我们的研究结果表明，次要 ZGA 的精确和及时调节受代谢动力学控制，并增强了我们对哺乳动物早期胚胎代谢的理解。