Elevating Pioneer transcription factor Nr5a2 expression promotes the development of mouse somatic cell nuclear transfer embryos

Somatic cell nuclear transfer (SCNT) is a valuable tool in regenerative medicine, yet its efficiency remains limited by epigenetic reprogramming barriers. SCNT embryos exhibit aberrant histone modifications, including H3K4me3, H3K9me3, H3K27me3, and H3K9ac, which can be partially corrected by regulating epigenetic enzymes. However, these approaches lack locus specificity and may disrupt normal gene regulation. Additionally, imprinting defects, such as aberrant Xist expression and loss of H3K27me3-dependent imprinting, further impair SCNT development. While targeted gene corrections improve outcomes, their effects are limited due to the extensive dysregulation of genes. Here, we investigated whether the pioneer transcription factor could enhance SCNT efficiency by facilitating an open chromatin state. Our study demonstrates that pioneer transcription factor Nr5a2 overexpression in SCNT embryos improves both zygotic genome activation and the morula-to-blastocyst transition, two major developmental barriers in SCNT, and enhances birth rates. Mechanistically, Nr5a2 recruits P300 to increase H3K27ac at low-expression genes, restoring transcriptional activity and promoting SCNT embryo development.