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bioRxiv · 10.1101/2025.10.07.680892

Maternal SETDB1 enables development beyond cleavage stages by extinguishing the MERVL-driven 2-cell totipotency transcriptional program in the mouse embryo

Zeng, T.-B.·Fu, Z.·Majewski, M. F.·Liao, J.·Adams, M.·Szabo, P. E.
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Abstract

Loss of maternal SETDB1, a histone H3K9 methyltransferase, leads to developmental arrest prior to implantation, with very few mouse embryos advancing beyond the 8-cell stage, which is currently unexplained. We genetically investigate SETDB1s role in the epigenetic control of the transition from totipotency to pluripotency--a process demanding precise timing and forward directionality. Through single-embryo total RNA sequencing of 2-cell and 8-cell embryos, we find that Setdb1mat-/+ embryos fail to extinguish 1-cell and 2-cell transient genes--alongside persistent expression of MERVL retroelements and MERVL-driven chimeric transcripts that define the totipotent state in mouse 2-cell embryos. Comparative bioinformatics reveals that SETDB1 acts at MT2 LTRs and MERVL-driven chimeric transcripts, which normally acquire H3K9me3 during early development. The dysregulated targets substantially overlap with DUXBL-responsive genes, indicating a shared regulatory pathway for silencing the 2-cell transcriptional program. We establish maternal SETDB1 as a critical chromatin regulator required to extinguish retroelement-driven totipotency networks and ensure successful preimplantation development.

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Zeng, T.-B., Fu, Z., Majewski, M. F., Liao, J., Adams, M., Szabo, P. E.. 2025-10-09. Maternal SETDB1 enables development beyond cleavage stages by extinguishing the MERVL-driven 2-cell totipotency transcriptional program in the mouse embryo. https://doi.org/10.1101/2025.10.07.680892

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