Cytoplasmic mRNA levels are regulated by a combination of chromatin retention and RNA stability

Abstract

ABSTRACTTranscription and co-transcriptional processes, including pre-mRNA splicing and mRNA cleavage and polyadenylation, regulate the production of mature mRNAs. The carboxyl terminal domain (CTD) of RNA polymerase (pol) II, which comprises 52 repeats of the Tyr1Ser2Pro3Thr4Ser5Pro6Ser7 peptide, is involved in the coordination of transcription with co-transcriptional processes. The pol II CTD is dynamically modified by protein phosphorylation, which regulates recruitment of transcription and co-transcriptional factors. We have investigated whether cytoplasmic levels of mature mRNA from intron-containing protein-coding genes are related to pol II CTD phosphorylation, RNA stability, and pre-mRNA splicing and mRNA cleavage and polyadenylation efficiency. We find that genes that produce a low level of mature mRNA are associated with relatively high phosphorylation of the pol II CTD Tyr1 and Thr4 residues, poor RNA processing, increased chromatin retention, and shorter RNA half-life. While these poorly-processed transcripts are degraded by the nuclear RNA exosome, our results indicate that in addition to RNA half-life, chromatin retention due to a low RNA processing efficiency also plays an important role in the regulation of cytoplasmic mRNA levels.