{"doi":"10.1016/j.jhep.2024.03.043","title":"Polyploidisation pleiotropically buffers ageing in hepatocytes","abstract":"<h4>Background & aims</h4>Polyploidy in hepatocytes has been proposed as a genetic mechanism to buffer against transcriptional dysregulation. Here, we aim to demonstrate the role of polyploidy in modulating gene regulatory networks in hepatocytes during ageing.<h4>Methods</h4>We performed single-nucleus RNA sequencing in hepatocyte nuclei of different ploidy levels isolated from young and old wild-type mice. Changes in the gene expression and regulatory network were compared to three independent strains that were haploinsufficient for HNF4A, CEBPA or CTCF, representing non-deleterious perturbations. Phenotypic characteristics of the liver section were additionally evaluated histologically, whereas the genomic allele composition of hepatocytes was analysed by BaseScope.<h4>Results</h4>We observed that ageing in wild-type mice results in nuclei polyploidy and a marked increase in steatosis. Haploinsufficiency of liver-specific master regulators (HFN4A or CEBPA) results in the enrichment of hepatocytes with tetraploid nuclei at a young age, affecting the genomic regulatory network, and dramatically suppressing ageing-related steatosis tissue wide. Notably, these phenotypes are not the result of subtle disruption to liver-specific transcriptional networks, since haploinsufficiency in the CTCF insulator protein resulted in the same phenotype. Further quantification of genotypes of tetraploid hepatocytes in young and old HFN4A-haploinsufficient mice revealed that during ageing, tetraploid hepatocytes lead to the selection of wild-type alleles, restoring non-deleterious genetic perturbations.<h4>Conclusions</h4>Our results suggest a model whereby polyploidisation leads to fundamentally different cell states. Polyploid conversion enables pleiotropic buffering against age-related decline via non-random allelic segregation to restore a wild-type genome.<h4>Impact and implications</h4>The functional role of hepatocyte polyploidisation during ageing is poorly understood. Using single-nucleus RNA sequencing and BaseScope approaches, we have studied ploidy dynamics during ageing in murine livers with non-deleterious genetic perturbations. We have identified that hepatocytes present different cellular states and the ability to buffer ageing-associated dysfunctions. Tetraploid nuclei exhibit robust transcriptional networks and are better adapted to genomically overcome perturbations. Novel therapeutic interventions aimed at attenuating age-related changes in tissue function could be exploited by manipulation of ploidy dynamics during chronic liver conditions.","journal":"Journal of Hepatology","year":2024,"id":10547,"datarank":0.5271928273695872,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.1544568299013871,"self_endowment_contribution":0.37273599746820013,"citer_contribution":0.1544568299013871,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":10,"citers_with_citation_signal":10,"citers_with_endowment":10,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0375,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-08-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":3572,"name":"Maren Büttner","orcid":"0000-0002-6189-3792","position":1,"is_corresponding":false},{"id":84299,"name":"Ioannis K. Deligiannis","orcid":"0000-0001-7498-0804","position":2,"is_corresponding":false},{"id":87381,"name":"Mateusz Strzelecki","orcid":"0000-0002-7584-0843","position":3,"is_corresponding":false},{"id":87382,"name":"Liwei Zhang","orcid":null,"position":4,"is_corresponding":false},{"id":42,"name":"Fabian Joachim Theis","orcid":"0000-0002-2419-1943","position":6,"is_corresponding":false},{"id":28294,"name":"Duncan T. Odom","orcid":"0000-0001-6201-5599","position":7,"is_corresponding":false},{"id":79297,"name":"Celia P. Martinez-Jimenez","orcid":null,"position":8,"is_corresponding":false},{"id":1700,"name":"Carlos Talavera‐López","orcid":"0000-0001-8590-2393","position":9,"is_corresponding":false},{"id":79302,"name":"Celia Pilar Martinez‐Jimenez","orcid":"0000-0002-9534-6201","position":10,"is_corresponding":false},{"id":87380,"name":"Kelvin Yin","orcid":"0000-0003-2993-6374","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"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":[]}