Cytoplasmic mRNA decay by the anti-viral nuclease RNase L promotes transcriptional repression [4sU-seq]

Ribonuclease (RNase) L is an antiviral factor that promiscuously degrades viral and cellular RNA in the cytoplasm. This results in extensive translational reprogramming, altering mRNA processing and export. Here, we reveal that another major consequence of cytoplasmic RNase L activity is the repression of nascent RNA synthesis in the nucleus. This is not associated with altered nuclear RNA stability but instead results from transcriptional repression. For RNA polymerase II, repression is primarily associated with reduced occupancy of serine 2-phosphorylated polymerase in gene bodies, indicating an elongation defect. Prominent among the transcriptionally downregulated loci are immune-related genes, supporting a role for RNase L in tempering innate immune and inflammatory responses. RNase L activation also caused disruption of nucleoli and reduced RNA polymerase I and III transcription. Crosstalk between RNA decay and transcription thereby contributes to the large-scale modulation of gene expression in RNase L-activated cells. Overall design: Nascent RNA profiling by 4sU-seq of A549 WT or RNase L-KO cells either transfected with Lipofactamine RNAiMAX alone or with poly(I:C) for 4 hours (3 biological replicates per condition).