Endogenous retroviruses synthesize heterologous chimeric RNAs to reinforce human early embryo development (4C-MLT2A1-RNA-OE)

Zygotic genome activation is critical for early embryogenesis, and its failure results in developmental arrest, posing a clinical challenge to women's fertility. Here we show that in vitro fertilized human embryos ceased development at 8-Cell ZGA stage are associated with a specific down-regulation of an endogenous retrovirus, MLT2A1. The depletion of MLT2A1 causes a failure in embryo development and reduction in ZGA gene expression. Mechanistically, we uncover that MLT2A1s synthesize chimeric transcripts with both coding and non-coding sequences, while predominantly fusing with downstream heterologous retrotransposons. While these diverse fusion sequences expand the genome-targeting spectrum of MLT2A1 RNAs, the shared MLT2A1 sequences partner with HNRNPU to recruit RNA Pol II to promote transcription. This enables MLT2A1 to broadly target and activate global ZGA genes, alongside amplifying its own sub-family expression. Our study uncovers an interlocking network formed by MLT2A1 chimeric RNAs, which act synergistically to boost global ZGA transcription and reinforce human early embryogenesis.