Obox4secures zygotic genome activation upon loss ofDux

Abstract

AbstractOnce fertilized, mouse zygotes rapidly proceed to zygotic genome activation (ZGA), during which long terminal repeats (LTRs) of murine endogenous retroviruses with leucine tRNA primer (MERVL) are potently activated by a conserved homeodomain-containing transcription factor, DUX. However,Dux-knockout embryos produce fertile mice, suggesting that ZGA is redundantly driven by an unknown factor(s). In the present study, we present multiple lines of evidence that the multicopy mouse homeobox gene,Obox4, encodes a transcription factor that is highly expressed in mouse 2-cell embryos and redundantly drives ZGA. Single depletion ofObox4orDuxis tolerated by embryogenesis, whereasObox4/Duxdouble depletion completely compromises embryonic development. Genome-wide epigenetic profiling revealed that OBOX4 binds to MERVL LTRs as well as a subset of murine endogenous retroviruses with lysine tRNA primer (MERVK) LTRs, and mediates the deposition of active histone modifications. Our study identified OBOX4 as a transcription factor that provides genetic redundancy to pre-implantation development.