Research Associate Professor Tongji University Shanghai, Shanghai, China (People's Republic)
Abstract: Achieving successful cloning via somatic cell nuclear transfer (SCNT) encounters substantial hurdles due to epigenetic impediments. Emerging research has pinpointed the roles of H3K4me3 and H3K27me3 as likely contributors to these challenges. Nonetheless, the precise mechanisms behind these obstacles remain largely enigmatic. In this study, we characterized the landscapes of H3K4me3 and H3K27me3 during pre-implantation development of SCNT embryos. Comparative analysis with naturally fertilized (NF) embryos uncovered aberrant overabundance of both H3K4me3 and H3K27me3 in NT embryos at 2-cell stage, leading to severe expression defects in ZGA genes with a bivalent state. By contrast, H3K36me3, which is mutually exclusive with H3K4me3/H3K27me3, showed deficient establishment in NT 2-cell embryos. Importantly, overexpression of Setd2, a methyltransferase of H3K36me3, effectively rescued the expression of ZGA genes in NT embryos and benefited embryo development. Mechanistically, SETD2 facilitated these genes escape from H3K4me3/H3K27me3 bivalency, by augmenting H3K36me3 marks at gene bodies and further squeezing H3K27me3 out of promoters. In summary, our data underscore the excessive bivalent state at gene promoters as a formidable impediment during somatic cell reprogramming. The removal of such barriers is a promising strategy for advancing cloning efficiency.
