Homeostasis of mRNA concentrations through coupling transcription, export, and degradation

Many experiments showed that eukaryotic cells maintain a constant mRNA concentration upon various perturbations by actively regulating mRNA production and degradation rates, known as mRNA buffering. However, the underlying mechanism is still unknown. In this work, we unveil a mechanistic model of mRNA buffering: the releasing-shuttling (RS) model. The model incorporates two crucial proteins, X and Y, which play several roles, including transcription, decay, and export factors, in the different stages of mRNA metabolism. The RS model predicts the constant mRNA concentration under genome-wide genetic perturbations and cell volume changes, the slowed-down mRNA degradation after Pol II depletion, and the temporal transcription dynamics after exonuclease depletion, in agreement with multiple experiments. Finally, we present a list of X and Y candidates and propose an experimental method to identify X. Our work uncovers potentially universal pathways coupling transcription, export, and degradation that help cells maintain mRNA homeostasis.