Metabolic and epigenetic dysfunctions underlie the arrest of in vitro fertilized human embryos in a senescent-like state.
Metabolic and epigenetic dysfunctions underlie the arrest of in vitro fertilized human embryos in a senescent-like state.
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DOI：
10.1371/journal.pbio.3001682
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发表时间：
2022-06
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
大约 60% 的体外受精 (IVF) 人类胚胎在 3 至 8 细胞阶段压缩之前会不可逆地停滞，这造成了重大的临床问题。这次逮捕背后的机制尚不清楚。在这里，我们发现停滞的胚胎进入类衰老状态，其标志是细胞周期停滞、核糖体和组蛋白的下调以及 MYC 和 p53 活性的下调。被阻滞的胚胎可分为3种类型。 I 型胚胎无法完成母体-合子转变，II/III 型胚胎糖酵解水平较低，氧化磷酸化水平较高（II 型）或较低（III 型）。使用 SIRT 激动剂白藜芦醇或烟酰胺核苷 (NR) 治疗可以部分挽救停滞的表型，这种表型伴随着代谢活动的变化。总的来说，我们的数据表明代谢和表观遗传功能障碍是人类胚胎停滞的原因。人类胚胎在体外发育不良，多达60%的胚胎会不可逆地停滞。这项研究表明，停滞的胚胎进入了类似衰老的状态，并揭示了与合子基因组激活问题和错误代谢相关的几种机制至少可以部分解释这种停滞背后的一些原因。
Around 60% of in vitro fertilized (IVF) human embryos irreversibly arrest before compaction between the 3- to 8-cell stage, posing a significant clinical problem. The mechanisms behind this arrest are unclear. Here, we show that the arrested embryos enter a senescent-like state, marked by cell cycle arrest, the down-regulation of ribosomes and histones and down-regulation of MYC and p53 activity. The arrested embryos can be divided into 3 types. Type I embryos fail to complete the maternal-zygotic transition, and Type II/III embryos have low levels of glycolysis and either high (Type II) or low (Type III) levels of oxidative phosphorylation. Treatment with the SIRT agonist resveratrol or nicotinamide riboside (NR) can partially rescue the arrested phenotype, which is accompanied by changes in metabolic activity. Overall, our data suggests metabolic and epigenetic dysfunctions underlie the arrest of human embryos. Human embryos develop poorly in vitro, and as much as 60% of embryos will irreversibly arrest. This study shows that the arrested embryos enter a senescent-like state, and reveals that several mechanisms related to zygotic genome activation problems and erroneous metabolism can at least partly explain some of the reasons behind this arrest.
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