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Induction of cellular totipotency by NACC1-driven feed-forward regulation.

Meharwade, T.; Duran-Bishop, G.; Joumier, L.; Dhakal, S.; Usama, M.; Jagdish, S.; Lambert, E.; Kherdjemil, Y.; Robert, F.; Malleshaiah, M.

2025-10-15 developmental biology
10.1101/2025.10.14.682353 bioRxiv
Show abstract

Mammalian embryo development begins with totipotent cells. Despite its significance, gene regulatory mechanisms controlling the totipotent cell stage are poorly understood. Based on single-cell proteomics and transcriptomics, we identified nucleus accumbens-associated 1 (NACC1) as a critical regulator of totipotent-like cell state in mouse embryonic stem cells. Using a combination of genomics approaches, we found that NACC1 directly binds to gene-regulatory regions and favours chromatin accessibility to induce the expression of totipotency and zygotic genome activation genes, as well as retrotransposons associated with totipotency. In parallel, NACC1-regulated retrotransposons further modulate the expression of proximal totipotency genes, forming a coherent feed-forward mechanism that regulates totipotent-like cells. Furthermore, NACC1 is crucial for the progression of embryogenesis beyond the totipotency stage. Thus, we uncover a genome-level NACC1-driven feed-forward gene regulatory mechanism that governs totipotent-like cells and has a crucial role during embryonic development.

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