Human in vitro fertilized embryos exhibit low developmental capabilities, and the mechanisms that underlie embryonic arrest remain unclear. Here using a single-cell multi-omics sequencing approach, we simultaneously analysed alterations in the transcriptome, chromatin accessibility and the DNA methylome in human embryonic arrest due to unexplained reasons. Arrested embryos displayed transcriptome disorders, including a distorted microtubule cytoskeleton, increased genomic instability and impaired glycolysis, which were coordinated with multiple epigenetic reprogramming defects. We identified Aurora A kinase (AURKA) repression as a cause of embryonic arrest. Mechanistically, arrested embryos induced through AURKA inhibition resembled the reprogramming abnormalities of natural embryonic arrest in terms of the transcriptome, the DNA methylome, chromatin accessibility and H3K4me3 modifications. Mitosis-independent sequential activation of the zygotic genome in arrested embryos showed that YY1 contributed to human major zygotic genome activation. Collectively, our study decodes the reprogramming abnormalities and mechanisms of human embryonic arrest and the key regulators of zygotic genome activation.

人类体外受精胚胎的发育能力较低，胚胎停滞的机制仍不清楚。在这里，我们使用单细胞多组学测序方法，同时分析了人类胚胎停滞中由于无法解释的原因导致的转录组、染色质可及性和 DNA 甲基化组的变化。停滞的胚胎表现出转录组疾病，包括微管细胞骨架扭曲、基因组不稳定性增加和糖酵解受损，这些都与多种表观遗传重编程缺陷相协调。我们发现极光 A 激酶 (AURKA) 抑制是胚胎停滞的一个原因。从机制上讲，通过 AURKA 抑制诱导的停滞胚胎在转录组、DNA 甲基化组、染色质可及性和 H3K4me3 修饰方面类似于自然胚胎停滞的重编程异常。停滞胚胎中合子基因组的不依赖有丝分裂的顺序激活表明，YY1 有助于人类主要合子基因组的激活。总的来说，我们的研究解码了人类胚胎停滞的重编程异常和机制以及合子基因组激活的关键调节因子。