New findings offer insight into why some embryos fail to develop past zygotic genome activation (ZGA), pointing to an unexpected root of human infertility. A critical point in early development is zygotic genome activation (ZGA), a milestone that marks the transition from reliance on maternal factors to activation of its own genome. This process requires a comprehensive reshaping of chromatin and transcription networks. Failures in ZGA are a major cause of early embryo arrest and contribute to cases of infertility and pregnancy loss. Previous research has shown that endogenous retroviruses (ERVs) – genetic remnants of ancient viral infections – become highly active during development and contribute substantially to the embryo’s transcriptome. Some ERV families produce large amounts of RNA during ZGA. However, the roles of these ERV-derived RNAs in ZGA and early embryo development remain unclear. Yangquan Xiang and colleagues examined human embryos arrested at the 8-cell stage and discovered a central role for the totipotency-specific retroviral element, MLT2A1, which produces diverse noncoding chimeric RNAs that work together to drive the large-scale awakening of the embryo’s own genes during ZGA. According to Xiang et al., MLT2A1 RNAs function as a coordinated network that can target many sites across the genome and amplify one another’s activity to reinforce the gene activation required for successful development. When MLT2A1 expression is reduced, as typically seen in embryos arrested at the 8-cell stage, ZGA is impaired and embryo development fails, highlighting the ERV’s importance.
