Chromatin accessibility memory of donor cells disrupts bovine somatic cell nuclear transfer blastocysts development

The post-transfer developmental capacity of bovine somatic cell nuclear transfer (SCNT) blastocysts is reduced, implying the still presence of abnormalities in the regulation of gene expression even though they can survive to blastocyst stage. Chromatin accessibility provides valuable information on the regulatory elements and gene transcription activity, which has heretofore been largely unexplored in SCNT embryos. To investigate the abnormalities in SCNT blastocysts, we performed single-cell ATAC-seq on in vivo and SCNT blastocysts to segregate lineages and found the SCNT blastocysts have compromised inner cell mass (ICM) which exhibits variants in the pattern and dynamics of chromatin accessibility. A portion of the aberrant accessibility of SCNT blastocysts were inherited from the accessibility memory of donor cells. Typically, the aberrantly accessible regions in ICM of SCNT blastocysts were enriched for H3K4me3 in the corresponding genomic locus in donor cells, which were identified as active memory regions. Removal of excessive H3K4me3 by KDM5B overexpression could correct the abnormal accessibility of ICM-AMRs and the expression of related genes, accompanied by a significantly improved ICM lineage of SCNT blastocysts.