Kinetics of mRNA nuclear export regulate innate immune response gene expression
Diane Lefaudeux, Supriya Sen, Kevin Jiang, Alexander Hoffmann, the UCLA Ribonomics Group, Jose Guillermo Sanchez Arriola, Nick Miller, Cheng Zhang, Emily Yi Hsin Chen, Sukanya Roy, Roberto Spreafico, Tracy Johnson, Erin M. Wissink, Shubhamoy Ghosh, Douglas L. Black, Chia-Ho Lin, Xinshu Xiao, Jae Hoon Bahn, Ashley Cass, Esther Y. H. Hsiao, Stephen T. Smale, Jerry Hung-Hao Lo, Jason Ernst, Artur Jaroszewicz, Matteo Pellegrini, Marco Morselli, Yi Xing, Eddie Park, Sri Kosuri
Abstract
The abundance and stimulus-responsiveness of mature mRNA is thought to be determined by nuclear synthesis, processing, and cytoplasmic decay. However, the rate and efficiency of moving mRNA to the cytoplasm almost certainly contributes, but has rarely been measured. Here, we investigated mRNA export rates for innate immune genes. We generated high spatio-temporal resolution RNA-seq data from endotoxin-stimulated macrophages and parameterized a mathematical model to infer kinetic parameters with confidence intervals. We find that the effective chromatin-to-cytoplasm export rate is gene-specific, varying 100-fold: for some genes, less than 5% of synthesized transcripts arrive in the cytoplasm as mature mRNAs, while others show high export efficiency. Interestingly, effective export rates do not determine temporal gene responsiveness, but complement the wide range of mRNA decay rates; this ensures similar abundances of short- and long-lived mRNAs, which form successive innate immune response expression waves.