| First Author | Zeng TB | Year | 2026 |
| Journal | Elife | Volume | 15 |
| PubMed ID | 41697236 | Mgi Jnum | J:382386 |
| Mgi Id | MGI:8291032 | Doi | 10.7554/eLife.109248 |
| Citation | Zeng TB, et al. (2026) SETDB1 enables development beyond cleavage stages by extinguishing the MERVL-driven two-cell totipotency transcriptional program in the mouse embryo. Elife 15 |
| abstractText | Loss of maternal SETDB1, a histone H3K9 methyltransferase, leads to developmental arrest prior to implantation, with very few mouse embryos advancing beyond the eight-cell stage, which is currently unexplained. We genetically investigate SETDB1's 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 two-cell and eight-cell embryos, we find that Setdb1(mat-/+) embryos fail to extinguish one-cell and two-cell transient genes-alongside persistent expression of MERVL retroelements and MERVL-driven chimeric transcripts that define the totipotent state in mouse two-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 two-cell transcriptional program. We establish maternal SETDB1 as a critical chromatin regulator required to extinguish retroelement-driven totipotency networks and ensure successful preimplantation development. |
