The chromatin associated proteins HP1 behave as liver specific tumour suppressors in mice. Mus musculus

Purpose : In this study we observed that inactivation of the genes encoding for the chromatin associated proteins HP1 lead to a highly increased predisposition of mice to develop tumours within liver. The purpose of this analysis was to identify and characterize genes whose expression was altered early on within livers of the HP1 mutant mice that could explain the tumorigenesis phenotype observed in very old animals. Results : this analysis revealed that only few genes (129 for HP1αKO, 84 for HP1αβliverKO and 87 for HP1αγliverKO) displayed differential expression between control and mutant animals [with a threshold of 1.5 fold difference and an adjusted pvalue≤0.05]. Besides several genes putatively involved in tumorigenesis, we found a significant enrichment in genes encoding several members of the family of transcriptional repressors KRAB-ZFP and presented data arguing that this increased expression resulted from their own loss of repressive activity because of the loss of interaction between their corepressor TRIM28 and HP1. Conclusions: our study represents the first demonstration that HP1 behave as tumour suppressors within liver and provide a comprehensive analysis of the underlying molecular mechanisms suggesting that HP1 main function within liver is to allow an appropriately regulated activity of the KRAB-ZFP/TRIM28/HP1 axis essential for liver homeostasis. Overall design: RNA profile of livers from 5 week old WT, HP1aKO, HP1abKO and HP1agKO mice were generated by Illumina RNA sequencing