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.

doi:10.1101/2025.10.14.682353

bioRxiv · 10.1101/2025.10.14.682353

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.

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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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Meharwade, T., Duran-Bishop, G., Joumier, L., Dhakal, S., Usama, M., Jagdish, S., Lambert, E., Kherdjemil, Y., Robert, F., Malleshaiah, M.. 2025-10-15. Induction of cellular totipotency by NACC1-driven feed-forward regulation.. https://doi.org/10.1101/2025.10.14.682353

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