Chromatin organization is essential for appropriate interpretation of the genetic information. Here, we demonstrated that the chromatin associated proteins HP1 are dispensable for cell survival but are essential within hepatocytes to prevent liver tumor development. Molecular characterization of pre-malignant HP1-Triple KO livers revealed that HP1 are essential for the maintenance of the structural organization of heterochromatin but surprisingly, not for several well known heterochromatin functions such as the maintenance of the genome stability nor the regulation of major satellite repeat expression within liver. We further show that some specific retrotransposons, mainly of the ERV family, get reactivated in HP1-TKO livers correlating, in some cases, with the activation of the adjacent genes. We present evidence that this reactivation of ERV relies on the HP1-dependent ability of the corepressor TRIM28 to regulate KRAB-ZFP repressive activity. Intriguingly, we found that in contrast to the observation in young animals, the HP1-dependent maintenance of ERV silencing becomes independent of TRIM28 in old animals. Finally, we showed that HP1 are also essential directly or indirectly for the regulation of single genes with most of them having well characterized functions in liver homeostasis such as regulation of the redox and endoplasmic reticulum equilibrium, lipid metabolism and steroid biosynthesis.Altogether, our findings indicate that HP1 proteins, through the modulation of multiple chromatin-associated events both within the heterochromatic and euchromatic compartments, act as guardians of liver homeostasis to prevent tumor development.

The mouse HP1 proteins are essential for preventing liver tumorigenesis