Analysis for the publication: Polyploidisation pleiotropically buffers ageing in hepatocytes (Yin K., Büttner M., et al. 2024) [1]
Polyploidy in hepatocytes has been proposed as a genetic mechanism to buffer against transcriptional dysregulation. Here, we demonstrate in wild-type mice, that hepatocytes with tetraploid nuclei attenuate age-related changes in gene expression and regulatory network structure. In hepatocytes, haploinsufficiency of liver-specific master regulators (HNF4A or CEPBA) is a non-deleterious perturbation, which we found resulted in early tetraploidisation and dramatic suppression of age-related steatosis. 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. By quantifying the genotypes of tetraploid hepatocytes in young and old HNF4A haploinsufficient mice, we discovered that polyploidy results in the selection for wild-type alleles during ageing. Our results suggest a model whereby polyploidisation leads to fundamentally different cell states, where polyploid conversion enables pleiotropic buffering against age related decline via non-random allelic segregation to restore a wild-type genome.
All raw sequencing data from old and haploinsufficient mice is deposited and publicly available in ArrayExpress/Biostudies under accession number E-MTAB-12738. [2]
Raw sequencing data from young wild type mice was obtained from our previous work deposited in ArrayExpress under accession number E-MTAB-9333. [3]
This pipeline has been developed by Dr. Maren Bütter and is adapted from our previous publication [4] and the scanpy standard methods.
[1] Yin K., Büttner M., at al. Polyploidisation pleiotropically buffers ageing in hepatocytes.
[2] Yin K., Büttner M., Deligiannis IK., Strzelecki M., Zhang L., Talavera-López C., et al. Hepatocyte polyploidization during ageing protects against transcriptional dysregulation and chronic liver disease. ArrayExpress/Biostudies, E-MTAB-12738 2023; https://www.ebi.ac.uk/biostudies/studies/E-MTAB-12738
[3] Deligiannis IK., Martinez-Jimenez C. Single-nucleus RNA-seq2 of liver tissue of 3 months old mice to investigate crosstalk between ploidy and zonation. ArrayExpress/BioStudies, E-MTAB-9333 2021; https://www.ebi.ac.uk/biostudies/arrayexpress/studies/E-MTAB-9333
[4] Richter, M.L., Deligiannis, I.K., Yin, K. et al. Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy. Nat Commun 12, 4264 (2021). https://doi.org/10.1038/s41467-021-24543-5