Nuclear RNA exosome targeting onto chromatin loci in the degradation of unstable transcripts affects transcriptional programs in liver cells.

Abstract

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 HP1s impact on RNA turnover contributes to its function in cancer biology.