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Published on: January 26, 2013
The homeobox transcription factor DUXBL controls exit from totipotency
Maria Vega-Sendino1, Felipe F Lüttmann2,3, Teresa Olbrich1
1Laboratory of Genome Integrity, CCR, NCI, NIH, Bethesda, MD, USA.
Abstract:
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.
Insights
The double homeobox protein B (DUXBL) protein silences early embryonic gene expression. DUXBL deficiency in mice causes developmental arrest by preventing exit from the totipotent two-cell (2C) stage.
Area of Science:
- Developmental Biology
- Genetics
- Epigenetics
Background:
- Exit from the totipotent two-cell (2C) stage in mouse embryos requires silencing of 2C-associated genes.
- The molecular mechanisms regulating this crucial silencing event are not fully understood.
Purpose of the Study:
- To elucidate the role of DUXBL in regulating the exit from the 2C stage in mouse embryonic development.
- To identify the molecular mechanisms by which DUXBL controls 2C-associated transcription.
Main Methods:
- Investigated DUXBL's function in mouse embryonic stem cells and embryos.
- Utilized techniques including gene expression analysis, protein interaction studies, and DUXBL overexpression/inactivation models.
- Examined DUXBL's interaction with TRIM24 and TRIM33 and its colocalization in nuclear foci.
Main Results:
- DUXBL is induced by the 2C-specific transcription factor DUX, forming a negative feedback loop.
- DUXBL interacts with TRIM24 and TRIM33, facilitating gene silencing.
- DUXBL inactivation leads to sustained 2C transcription and early embryonic developmental arrest.
Conclusions:
- DUXBL is an essential regulator of the exit from embryonic totipotency.
- DUXBL's function is critical for the initial divergence of cell fates during early mammalian development.
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