GSE210890
The homeobox transcription factor DUXBL controls exit from the totipotent 2C state [Cut&Run]
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 determined that the 2C-specific transcription factor DUX directly induced the expression of DUXBL to promote this silencing. CUT&RUN analysis revealed that DUXBL gained accessibility to DUX-bound regions in DUX-induced ESC while it was unable to bind those regions in uninduced cells. Importantly, DUX expression in Duxbl-knockout ESC caused increased induction of the 2C-transcriptional program, whereas DUXBL overexpression impaired 2C-associated transcription. Mechanistically, we determined that DUXBL interacted with TRIM24 and TRIM33, two members of the tripartite motif superfamily involved in gene silencing, and co-localized with them in nuclear condensates upon DUX expression. Importantly, DUXBL downregulation in mouse zygotes led to a penetrant 2C-stage arrest. Our data revealed an unexpected role for DUXBL in controlling the exit from totipotency. Overall design: Cut&Run experiments of DUXBL, FLAG and H3K27ac in untreated or DOX-treated WT control, DUXBL or DUX/DUXBL expressing ESC. In addition, untreated or DOX-treated WT DUXBL-expressing ESC incubated with Pladienolide B for 24 hours.