Setd2 overexpression rescues bivalent gene expression during SCNT-mediated ZGA.

Xiaolei ZHANG; Ruimin XU; Yuyan ZHAO; Yijia YANG; Qi SHI; Hong WANG; Xiaoyu LIU; Shaorong GAO; Chong LI

Return

Setd2 overexpression rescues bivalent gene expression during SCNT-mediated ZGA.

Author: Xiaolei ZHANG ¹ ; Ruimin XU ¹ ; Yuyan ZHAO ¹ ; Yijia YANG ¹ ; Qi SHI ¹ ; Hong WANG ¹ ; Xiaoyu LIU ¹ ; Shaorong GAO ¹ ; Chong LI ¹
Author Information

1. Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translation Research Center, Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Publication Type:Journal Article
Keywords: SCNT; embryo development; histone modifications
MeSH: Animals; Mice; Histone-Lysine N-Methyltransferase/biosynthesis*; Histones/genetics*; Nuclear Transfer Techniques; Female; Gene Expression Regulation, Developmental; Promoter Regions, Genetic; Epigenesis, Genetic; Embryo, Mammalian/metabolism*
From: Protein & Cell 2025;16(6):439-457
CountryChina
Language:English
Abstract: Successful cloning through somatic cell nuclear transfer (SCNT) faces significant challenges due to epigenetic obstacles. Recent studies have highlighted the roles of H3K4me3 and H3K27me3 as potential contributors to these obstacles. However, the underlying mechanisms remain largely unclear. In this study, we generated genome-wide maps of H3K4me3 and H3K27me3 in mouse pre-implantation NT embryos. Our analysis revealed that aberrantly over-represented broad H3K4me3 domain and H3K27me3 signal lead to increased bivalent marks at gene promoters in NT embryos compared with naturally fertilized (NF) embryos at the 2-cell stage, which may link to relatively low levels of H3K36me3 in NT 2-cell embryos. Notably, the overexpression of Setd2, a H3K36me3 methyltransferase, successfully restored multiple epigenetic marks, including H3K36me3, H3K4me3, and H3K27me3. In addition, it reinstated the expression levels of ZGA-related genes by reestablishing H3K36me3 at gene body regions, which excluded H3K27me3 from bivalent promoters, ultimately improving cloning efficiency. These findings highlight the excessive bivalent state at gene promoters as a potent barrier and emphasize the removal of these barriers as a promising approach for achieving higher cloning efficiency.