TY  - JOUR
AU  - Vega-Sendino, Maria
AU  - Lüttmann, Felipe F
AU  - Olbrich, Teresa
AU  - Chen, Yanpu
AU  - Kuenne, Carsten
AU  - Stein, Paula
AU  - Tillo, Desiree
AU  - Carey, Grace I
AU  - Zhong, Jiasheng
AU  - Savy, Virginia
AU  - Radonova, Lenka
AU  - Lu, Tianlin
AU  - Saykali, Bechara
AU  - Kim, Kee-Pyo
AU  - Domingo, Catherine N
AU  - Schüler, Leah
AU  - Günther, Stefan
AU  - Bentsen, Mette
AU  - Bosnakovski, Darko
AU  - Schöler, Hans
AU  - Kyba, Michael
AU  - Maity, Tapan K
AU  - Jenkins, Lisa M
AU  - Looso, Mario
AU  - Williams, Carmen J
AU  - Kim, Johnny
AU  - Ruiz, Sergio
TI  - The homeobox transcription factor DUXBL controls exit from totipotency.
JO  - Nature genetics
VL  - 56
IS  - 4
SN  - 1061-4036
CY  - London
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DKFZ-2024-00578
SP  - 697-709
PY  - 2024
N1  - 2024 Apr;56(4):697-709
AB  - In mice, exit from the totipotent two-cell (2C) stage embryo requires silencing of the 2C-associated transcriptional program. However, the molecular mechanisms involved in this process remain poorly understood. Here we demonstrate that the 2C-specific transcription factor double homeobox protein (DUX) mediates an essential negative feedback loop by inducing the expression of DUXBL to promote this silencing. We show that DUXBL gains accessibility to DUX-bound regions specifically upon DUX expression. Furthermore, we determine that DUXBL interacts with TRIM24 and TRIM33, members of the TRIM superfamily involved in gene silencing, and colocalizes with them in nuclear foci upon DUX expression. Importantly, DUXBL overexpression impairs 2C-associated transcription, whereas Duxbl inactivation in mouse embryonic stem cells increases DUX-dependent induction of the 2C-transcriptional program. Consequently, DUXBL deficiency in embryos results in sustained expression of 2C-associated transcripts leading to early developmental arrest. Our study identifies DUXBL as an essential regulator of totipotency exit enabling the first divergence of cell fates.
LB  - PUB:(DE-HGF)16
C6  - pmid:38509386
DO  - DOI:10.1038/s41588-024-01692-z
UR  - https://inrepo02.dkfz.de/record/289078
ER  -