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Yin, K. ; Büttner, M. ; Deligiannis, I.K. ; Strzelecki, M. ; Zhang, L. ; Talavera Lopez, C.N. ; Theis, F.J. ; Odom, D.T.* ; Martinez Jimenez, C.P.

Polyploidisation pleiotropically buffers ageing in hepatocytes.

J. Hepatol. 81, 289-302 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
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BACKGROUND & AIMS: 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. METHODS: 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 haploinsufficient strains 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. RESULTS: We observed that ageing in wild-type mice results in nuclei polyploidy and 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 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 perturbation. ConclusionsOur 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Basescope ; Liver ; Ageing ; Epigenetic Clock ; Haploinsufficiency ; Polyploidy ; Single-nucleus Rna-seq; Transcription Factor Network; Single-cell Analysis; Hepatic Steatosis; Fatty Liver; Gene-expression; Haploinsufficiency; Pancreas; Reveals; Differentiation; Replication
ISSN (print) / ISBN 0168-8278
e-ISSN 1600-0641
Journal Journal of Hepatology
Quellenangaben Volume: 81, Issue: 2, Pages: 289-302 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Helmholtz Pioneer Campus (HPC)
Institute of Computational Biology (ICB)
Grants Wellcome Trust
Helmholtz future topic Ageing and Metabolic Programming
CIDEGENT program
Janet Thornton Fellowship
ERC
Cancer Research UK
Helmholtz Pioneer Campus