Obox4promotes zygotic genome activation upon loss ofDux

Abstract

Once 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 pioneer factor, DUX. However, Dux-knockout embryos produce fertile mice, suggesting that ZGA is redundantly driven by unknown factor(s). In the present study, we report that the multicopy mouse homeobox gene, Obox4, encodes a transcription factor that redundantly drives ZGA. OBOX4 is highly expressed in mouse 2-cell embryos. Single knockdown of Obox4 or Dux is tolerated by embryogenesis, whereas Obox4/Dux double knockdown completely compromises embryonic development. Genome-wide epigenetic profiling revealed that OBOX4 binds to MERVL LTRs as well as murine endogenous retroviruses with lysine tRNA primer (MERVK) LTRs, and mediates the deposition of active histone modifications. Our study identified OBOX4 as a pioneer factor that provides genetic redundancy to pre-implantation development.

The homeobox transcription factor DUXBL controls exit from totipotency

“…Surprisingly, despite the prominent role of DUX in triggering a ZGA-associated signature in vitro, Dux -deficient mice are viable with mild pre- and post-implantation defects 20,21 . These observations revealed that DUX is important but largely dispensable for ZGA in mice and suggested that additional transcription factors, such as OBOX4, could compensate for its loss 22 .…”

Multiple repeat regions within mouse DUX recruit chromatin regulators to facilitate an embryonic gene expression program

“…DUX plays a key role in opening many promoters and enhancers, and in activating endogenous genes and repeat elements in the 2-cell embryo (38). DUX targets account for about 25% of the cleavage-stage transcriptome, and partly overlap with targets of OBOX4, underlying the observation that combined DUX and OBOX4 omission/depletion strongly affects embryo development (32).…”

“…However, as viable Dux -/pups are generated, factor(s) redundant with DUX appear to contribute to DUX target activation and chromatin reprogramming in 2-cell embryos (22,31). Recently, oocyte-specific homeobox 4 (OBOX4), a factor highly expressed during EGA and in 2C-like mESCs, has been identified as partly redundant with DUX in 2-cell embryos (32). Taken together, DUX and OBOX4 appear to cooperate to ensure proper EGA in the early mouse embryo.…”

The regulation of totipotency transcription: Perspective from in vitro and in vivo totipotency

“…Recently, a multi-copy mouse homeobox gene, Obox4, was identified, which potentially acted in parallel with Dux to initiate the ZGA network. Single knockdown of Obox4 or Dux was tolerated by embryogenesis, whereas Obox4/Dux double knockdown completely abolished embryonic development after 2C (Guo et al, 2022). Dux was rapidly degraded at the end of the 2C embryo stage, which is thought to be necessary for exit from the totipotency state both in vivo and in vitro.…”