Reproductive aging causes precocious ZGA and morula gene expression and chromatin hyper-activation in rhesus monkey embryos via maternal SETDB1 insufficiency

Maternal aging impairs embryo development. However, little is known regarding the molecular defects in aged human embryos. Combining single-cell RNA sequencing and ATAC-seq, we investigated aging-associated changes in the transcriptome and chromatin accessibility in fully grown GV oocytes, mature eggs, 4C, 8C, and morula embryos from young, middle-aged and old rhesus monkeys. We reveal that impaired maternal mRNA stability is a major RNA metabolism defect in aged oocytes. Unlike mice, aged monkey embryos display precocious expression of stage-specific genes including zygotic genome activation (ZGA) and morula-stage genes. Consistently, promoters and distal regulatory regions that show stage-specific accessibility changes in young embryos lose this dynamic regulation and become constitutively accessible in old embryos. Mechanistically, aged monkey embryos have reduced maternal transcripts of SETDB1 . Knockdown of SETDB1 in young monkey zygotes recapitulates aging-associated phenotypes. Thus, maternal SETDB1 insufficiency is a major factor contributing to developmental and molecular defects in aged embryos.