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

Abstract

Abstract Heterochromatin protein 1 (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 nuclear RNA exosome complexes, major RNA decay machineries. In mouse embryonic liver cells, inactivation of all three HP1 isoforms leads to accumulation of retrotransposon-derived RNAs and stabilization of enhancer RNAs. These changes coincide 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 collagen genes. Stratifying hepatocellular carcinoma samples by HP1 expression further reveal that tumors with low HP1 are 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.