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

The regulation of RNA maturation and degradation processes is crucial for maintaining cellular homeostasis, with defective regulation potentially leading to cancer or cellular senescence. RNA homeostasis occurs co-transcriptionally and is influenced by chromatin-associated factors, highlighting the need for further exploration in this area. HP1 proteins, originally identified as markers of pericentromeric heterochromatin, play significant roles in co-transcriptional processes occuring on chromatin. This study investigates the role of HP1 proteins in the maturation and degradation of non-coding RNAs, specifically focusing on their interaction with the RNA exosome, a key machinery for RNA degradation.

The effects of depleting all three HP1 isoforms were investigated in mouse embryonic liver (BMEL) cell lines. Our results demonstrate that the RNA exosome interacts with HP1 proteins and is targeted to chromatin loci through HP1-dependent mechanisms. Furthermore, the absence of HP1 proteins alters various RNA species genome-wide, reactivating transposon-like repeat elements and stabilizing certain gene-associated transcripts thereby found in cytoplasm. In human cells, patients with highest levels of inflammation show reduced HP1 levels and less RNA degradation. This reduction leads to tumors with unique characteristics, being more rigid and exhibiting lower proliferation, which makes them less deadly than tumors with high HP1 levels.

These findings illustrate the role of HP1 proteins in regulating RNA homeostasis through their interaction with the RNA exosome, suggesting important implications for cancer biology.