An Environmental Toxin-Based Approach to Revealing c-MYC as the Key Regulator of Embryo Compaction

Compaction is a pivotal developmental event during the preimplantation development of mammalian embryos. However, the mechanisms underlying the initiation of compaction, especially transcription factors, remain poorly understood. Here, we established an environmental chemical-based focused screening strategy to identify new regulators of compaction. Using a morula-like aggregate model derived from mouse extended pluripotent stem cells, we screened a targeted chemical library of environmental toxins associated with female reproductive toxicity and identified perfluorooctanoic acid (PFOA) as a compound that disrupts compaction. Importantly, PFOA inhibits compaction in both morula-like aggregate model and mouse early embryos by downregulating the activity of transcription factor c-MYC. Mechanistically, c-MYC regulates the miR-200/ZEB/E-cadherin axis which drives cell-cell adhesion during the compaction process of early embryos. Our study uncovers c-MYC as a key transcription factor in regulating compaction of mouse embryos, providing novel insight into the mechanism of compaction regulation. Overall design: RNA-seq profiling of morula-like aggregate model derived from mouse expanded pluripotent stem cells after treatment with PFOA or vehicle control.