Wang Jing, Zhou Cai, Gao Shuai, Song Xiuling, Yang Xinyan, Fan Jiaqi, Ren Shaofang, Ma Linzi, Zhao Jiexiang, Cui Manman, Song Ke, Wang Mei, Li Chaohui, Zheng Yi, Luo Fang, Miao Kai, Bai Xiaochun, Hutchins Andrew P, Li Lin, Chang Gang, Zhao Xiao-Yang
State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China.
Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, P. R. China.
Sci Adv. 2022 Aug 12;8(32):eabm3976. doi: 10.1126/sciadv.abm3976. Epub 2022 Aug 10.
Round spermatid injection (ROSI) technique holds great promise for clinical treatment of a proportion of infertile men. However, the compromised developmental potential of ROSI embryos largely limits the clinical application, and the mechanisms are not fully understood. Here, we describe the transcriptome, chromatin accessibility, and DNA methylation landscapes of mouse ROSI embryos derived from early-stage round spermatids using a single-cell multiomics sequencing approach. By interrogating these data, we identify the reprogramming defects in ROSI embryos at the pronuclear stages, which are mainly associated with the misexpression of a cohort of minor zygotic genome activation genes. We screen a small compound, A366, that can significantly increase the developmental potential of ROSI embryos, in which A366 can partially overcome the reprogramming defects by amending the epigenetic and transcriptomic states. Collectively, our study uncovers the reprogramming defects in ROSI embryos for understanding the mechanisms underlying compromised developmental potential and offers an avenue for ROSI technique optimization.
圆形精子细胞注射（ROSI）技术在临床上治疗一部分不育男性方面具有巨大潜力。然而，ROSI胚胎发育潜能受损在很大程度上限制了其临床应用，且相关机制尚未完全明确。在此，我们使用单细胞多组学测序方法描述了源自早期圆形精子细胞的小鼠ROSI胚胎的转录组、染色质可及性和DNA甲基化图谱。通过分析这些数据，我们确定了原核期ROSI胚胎中的重编程缺陷，这些缺陷主要与一组小的合子基因组激活基因的错误表达有关。我们筛选出一种小分子化合物A366，它能显著提高ROSI胚胎的发育潜能，其中A366可通过改善表观遗传和转录组状态部分克服重编程缺陷。总体而言，我们的研究揭示了ROSI胚胎中的重编程缺陷，有助于理解发育潜能受损的潜在机制，并为ROSI技术优化提供了一条途径。
