Dux-Mediated Corrections of Aberrant H3K9ac during 2-Cell Genome Activation Optimize Efficiency of Somatic Cell Nuclear Transfer

Differentiated somatic cells can be reprogrammed to totipotent embryos through somatic cell nuclear transfer (SCNT) with low efficiency. The histone deacetylase inhibitor trichostatin A (TSA) has been found to improve SCNT efficiency, but the underlying mechanism remains undetermined. Here, we examined genome-wide H3K9ac during SCNT embryo development and found that aberrant H3K9ac regions resulted in reduced 2-cell genome activation. TSA treatment largely corrects aberrant acetylation in SCNT embryos with an efficiency that is dictated by the native epigenetic environment. We further identified that the overexpression of Dux greatly improves SCNT efficiency by correcting the aberrant H3K9ac signal at its target sites, ensuring appropriate 2-cell genome activation. Intriguingly, the improvement in development mediated by TSA and Kdm4b is impeded by Dux knockout in SCNT embryos. Together, our study reveals that reprogramming of H3K9ac is important for optimal SCNT efficiency and identifies Dux as a crucial transcription factor in this process. [Display omitted] •Aberrant acetylated regions (AARs) are an epigenetic barrier in SCNT embryos•TSA partly fixes AARs but is restricted by native epi-environments in donor cells•Dux restores H3K9ac occupancy, drives 2C activation, and improves SCNT efficiency•Rescue efficiency by Kdm4b and TSA largely relies on Dux cluster activation Yang et al. show that aberrant H3K9ac functions as an epigenetic barrier for SCNT. TSA can partially fix AARs and promote SCNT reprogramming. However, this effect is restrained by the native epigenetic landscape. Dux, a crucial transcription factor, can overcome these limitations, boost 2-cell genome activation, and improve SCNT efficiency.