Targeting of the nuclear RNA exosome to chromatin by HP1 affects the transcriptional programs of liver cells

HP1, a hallmark of pericentromeric heterochromatin, is a chromatin-bound regulator of co-transcriptional processes including alternative splicing, but its role in RNA degradation remains unexplored. Here, we uncover a direct interaction between HP1 and the RNA exosome, a major RNA decay complex. In mouse embryonic liver cells, inactivation of all three HP1 isoforms led to accumulation of retrotransposon-derived RNAs and stabilization of enhancer RNAs. These changes coincided with increased activity at a subset of liver enhancers particularly sensitive to reduced exosome activity, many of which regulate genes encoding extracellular matrix components such as Col6a1 and Col6a2 . Stratifying hepatocellular carcinoma samples by HP1 expression further revealed that tumors with low HP1 were marked by reduced RNA degradation, and increased expression of a similar subset of genes encoding extracellular matrix components and possibly contributing to tumor stiffness. These results suggest that HP1’s impact on RNA turnover contributes to its function in cancer biology.