The production of mRNA is a dynamic process that is highly regulated by reversible post-translational modifications of the C-terminal domain (CTD) of RNA polymerase II. The CTD is a highly repetitive domain consisting mostly of the consensus heptad sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. Phosphorylation of serine residues within this repeat sequence is well studied, but modifications of all residues have been described. Here, we focus on integrating newly identified and lesser-studied CTD post-translational modifications into the existing framework. We also review the growing body of work demonstrating crosstalk between different CTD modifications and the functional consequences of such crosstalk on the dynamics of transcriptional regulation.

Importance

The hepatitis C virus (HCV) causes liver disease, affecting millions. Even though we have effective antivirals that cure HCV, they cannot stop terminal liver disease. We used an adult stem cell-derived liver organoid system to understand how HCV infection leads to the progression of terminal liver disease. Here, we show that HCV maintains low-grade infections in liver organoids for the first time. HCV infection in liver organoids leads to transcriptional reprogramming causing cancer cell development and altered immune response. Our finding shows how HCV infection in liver organoids mimics HCV infection and patient pathogenesis. These results reveal that HCV infection in liver organoids contributes to liver disease progression.