{"doi":"10.1101/2025.07.23.666394","title":"Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation","abstract":"Summary 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 ● CENP-A asymmetry between sperm and oocyte centromeres is a conserved feature from flies to mammals including mice and humans. ● CENP-A asymmetry between parental centromeres is resolved prior to the first zygotic division via maternally inherited, cytoplasmic CENP-A. ● Zygotic CENP-A levels in zygotes are regulated in a pronucleus-autonomous manner. ● CENP-A equalization relies on asymmetric CENP-C recruitment to the paternal pronucleus and requires CENP-C dimerization. Key Terms Centromere; CENP-A; CENP-C; sperm; oocyte; zygote; intergenerational; epigenetics; mouse","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558603,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":235830,"name":"Gabriel Manske","orcid":"0000-0001-5461-4647","position":1,"is_corresponding":false},{"id":1403098,"name":"Emily Lenk Ferrell","orcid":"0009-0008-9721-3868","position":2,"is_corresponding":false},{"id":814291,"name":"Dilara N. 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Black","orcid":"0000-0002-3707-9483","position":12,"is_corresponding":false},{"id":64732,"name":"Shawn L. Chavez","orcid":"0000-0002-8285-0222","position":13,"is_corresponding":false},{"id":109741,"name":"Erica E. Marsh","orcid":"0000-0003-1331-6525","position":14,"is_corresponding":false},{"id":237466,"name":"Ariella Shikanov","orcid":"0000-0003-0159-6419","position":15,"is_corresponding":false},{"id":298427,"name":"Karen Schindler","orcid":"0000-0001-6113-1184","position":16,"is_corresponding":false},{"id":463359,"name":"Xin Chen","orcid":"0000-0002-6990-0926","position":17,"is_corresponding":false},{"id":235835,"name":"Saher Sue Hammoud","orcid":"0000-0002-5040-6370","position":18,"is_corresponding":false},{"id":502949,"name":"Catherine A. Tower","orcid":"0000-0003-4470-6227","position":0,"is_corresponding":true}],"reference_count":107,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:25.969263Z","pmid":"40766472","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}