Polyploidisation pleiotropically buffers ageing in hepatocytes

单倍率不足 生物 表型 遗传学 老化 野生型 CTCF公司 等位基因 细胞生物学 基因敲除 基因 突变体 基因表达 增强子
作者
Kelvin Yin,Maren Büttner,Ioannis K. Deligiannis,Mateusz Strzelecki,Liwei Zhang,Carlos Talavera‐López,Fabian J. Theis,Duncan T. Odom,Celia Pilar Martinez‐Jimenez
出处
期刊:Journal of Hepatology [Elsevier BV]
卷期号:81 (2): 289-302 被引量:2
标识
DOI:10.1016/j.jhep.2024.03.043
摘要

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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