The homeobox transcription factor DUXBL controls exit from totipotency

Abstract

Upon exit from the totipotent 2-cell (2C) embryo stage, the 2C-associated transcriptional program needs to be efficiently silenced. However, the molecular mechanisms involved in this process remain mostly unknown. Here, we demonstrate that the 2C-specific transcription factor DUX directly induces the expression of DUXBL to promote this silencing. Indeed, DUX expression in Duxbl-knockout ESC causes increased induction of the 2C-transcriptional program, whereas DUXBL overexpression impairs 2C-associated transcription. CUT&RUN analyses show that DUXBL gains accessibility to DUX-bound regions in DUX-induced ESC while it is unable to bind those regions in uninduced cells. Mechanistically, we determined that DUXBL interacts with TRIM24 and TRIM33, two members of the tripartite motif superfamily involved in gene silencing and co-localizes with them in nuclear foci upon DUX expression. Furthermore, DUXBL downregulation in mouse zygotes leads to a penetrant 2C-stage arrest. Our data reveals an unexpected role for DUXBL in controlling the exit from totipotency.

Antagonism among DUX family members evolved from an ancestral toxic single homeodomain protein

“…Such feedback inhibition would serve to limit the temporal effect of a burst of DUX4 expression, explaining why the burst of DUX4 target genes in ZGA is so brief. We note that such a negative feedback role is also demonstrated for mouse DUXBL against mouse DUX in a companion study 34 . This feedback inhibition model stands in stark contrast to the previously suggested idea that DUXA serves to amplify or maintain the DUX4 signal after a burst of DUX4 23 .…”

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

“…This raises the possibility that the 'inactive' repeats may serve to attenuate the activity of the active repeats under certain conditions or at certain locations. Of note, DUX binds to its own promoter to help activate a strong positive feedback loop; however, Dux activation is brief (half a cell cycle), with silencing accompanying the association of the large Dux locus with the nucleolar envelope (38,39). Interestingly, we observe high enrichment of nucleolar components with the 'active' C3 repeat, raising the possibility that the 'active' repeat may initially recruit powerful chromatin and transcription factors, and then subsequently contribute to localizing the Dux locus to a compartment that overcomes and/or reverses those associations to enable Dux locus silencing (36).…”