Metabolic remodeling during early murine early embryo development

During early mammalian embryogenesis, dynamic changes in cell growth and proliferation are tightly linked to the underlying genetic and metabolic regulation. However, our understanding of metabolic reprogramming and its impact on epigenetic regulation in early embryo development remains elusive. We reconstruct their metabolic landscapes from the 2-cell and blastocyst stages, as well as their transition from totipotency to pluripotency. While 2-cell embryos favor methionine, polyamine and glutathione metabolism and stay in a more reductive state, blastocyst embryos have higher mitochondrial metabolites related to the tricarboxylic acid cycle, and present a more oxidative state. Moreover, we identify a reciprocal relationship between a-ketoglutarate (a-KG) and the competitive inhibitor of a-KG-dependent dioxygenases, L-2-hydroxyglutarate (2-HG), where 2-cell embryos inherited from oocytes and 1-cell zygotes display higher L-2-HG, whereas blastocysts show higher a-KG.Supplementing 2-HG or knocking down L2hgdh, a gene encoding the 2-HG consuming enzyme L-2-hydroxyglutarate dehydrogenase impeded erasure of global histone methylation markers . Together, our data demonstrate dynamic and interconnected metabolic, transcriptional and epigenetic network remodeling during murine early embryo development. Overall design: We have finished the RNA-seq to investigate the effect of 2-HG and a-KG on early mouse embryo from 2PN to blastocyst. The blastocyst was used to perform the high-throughput analysis.

在哺乳动物早期胚胎发生过程中，细胞生长与增殖的动态变化与内在的遗传及代谢调控紧密关联。然而，目前学界对于早期胚胎发育中的代谢重编程及其对表观遗传调控的影响仍缺乏清晰认知。本研究从2细胞期与囊胚期胚胎入手，重构了其从全能性（totipotency）向多能性（pluripotency）转变过程中的代谢图谱。2细胞期胚胎偏好甲硫氨酸（methionine）、多胺（polyamine）与谷胱甘肽（glutathione）代谢，处于更强的还原状态；而囊胚期胚胎则含有更多与三羧酸循环（tricarboxylic acid cycle）相关的线粒体代谢物，呈现出更显著的氧化状态。此外，本研究还发现α-酮戊二酸（a-ketoglutarate, α-KG）与其竞争性抑制剂L-2-羟戊二酸（L-2-hydroxyglutarate, 2-HG）之间存在互调控关系：由卵母细胞及1细胞合子继承而来的2细胞期胚胎中L-2-HG水平更高，而囊胚期胚胎则呈现更高水平的α-KG。补充2-HG或敲低编码2-HG代谢酶L-2-羟戊二酸脱氢酶的基因L2hgdh，会阻碍全局组蛋白甲基化标志物的清除过程。综上，本研究数据证实，在小鼠早期胚胎发育过程中存在动态且相互关联的代谢、转录及表观遗传网络重塑。实验整体设计：本研究通过RNA-seq探究2-HG与α-KG对2原核（2PN）至囊胚期小鼠早期胚胎的影响，以囊胚期胚胎为样本开展高通量分析。