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bioRxiv · 10.1101/2025.07.23.666394

Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation

Tower, C. A.·Manske, G.·Ferrell, E. L.·Anbarci, D. N.·Jorgensen, K.·Ma, B.·Aboelenain, M.·Ranjan, R.·Chakraborty, S.·Moritz, L.·Das, A.·Boiani, M.·Black, B. B.·Chavez, S.·Marsh, E. E.·Shikanov, A.·Schindler, K.·Chen, X.·Hammoud, S. S.
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Abstract

Across metazoan species, the centromere-specific histone variant CENP-A is essential for accurate chromosome segregation, yet its regulation at the parental-to-zygote transition in mammals is poorly understood. To address this, we developed a CENP-A-mScarlet knock-in mouse model, which revealed sex-specific dynamics: mature sperm retains 10% of the CENP-A levels present in MII-oocytes. However, in zygotes prior to the first mitosis, this difference is resolved, using maternally inherited cytoplasmic-CENP-A. Notably, the increase in CENP-A at paternal centromeres is independent of sensing CENP-A asymmetry or the presence of maternal chromosomes. Instead, CENP-A equalization relies on asymmetric recruitment of maternal CENP-C to paternal centromeres. Depletion of maternal CENP-A decreases total CENP-A in pronuclei without disrupting equalization. In contrast, reducing maternal CENP-C or disruption of its dimerization domains impairs CENP-A equalization and chromosome segregation. Therefore, maternal CENP-C acts a key epigenetic regulator that resets centromeric symmetry at fertilization to preserve genome integrity. Highlights[bullet] CENP-A asymmetry between sperm and oocyte centromeres is a conserved feature from flies to mammals including mice and humans. [bullet]CENP-A asymmetry between parental centromeres is resolved prior to the first zygotic division via maternally inherited, cytoplasmic CENP-A. [bullet]Zygotic CENP-A levels in zygotes are regulated in a pronucleus-autonomous manner. [bullet]CENP-A equalization relies on asymmetric CENP-C recruitment to the paternal pronucleus and requires CENP-C dimerization. Key TermsCentromere; CENP-A; CENP-C; sperm; oocyte; zygote; intergenerational; epigenetics; mouse

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Tower, C. A., Manske, G., Ferrell, E. L., Anbarci, D. N., Jorgensen, K., Ma, B., Aboelenain, M., Ranjan, R., Chakraborty, S., Moritz, L., Das, A., Boiani, M., Black, B. B., Chavez, S., Marsh, E. E., Shikanov, A., Schindler, K., Chen, X., Hammoud, S. S.. 2025-07-28. Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation. https://doi.org/10.1101/2025.07.23.666394

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