ABSTRACT
Diverse biological systems utilize gene-expression fluctuations (‘noise’) to drive lineage-commitment decisions1–5. However, once a commitment is made, noise becomes detrimental to reliable function6,7 and the mechanisms enabling post-commitment noise suppression are unclear. We used time-lapse imaging and mathematical modeling, and found that, after a noise-driven event, human immunodeficiency virus (HIV) strongly attenuated expression noise through a non-transcriptional negative-feedback circuit. Feedback is established by serial generation of RNAs from post-transcriptional splicing, creating a precursor-product relationship where proteins generated from spliced mRNAs auto-deplete their own precursor un-spliced mRNAs. Strikingly, precursor auto-depletion overcomes the theoretical limits on conventional noise suppression—minimizing noise far better than transcriptional auto-repression—and dramatically stabilizes commitment to the active-replication state. Such RNA-mediated auto-depletion feedback may efficiently suppress noise in other systems ranging from detained introns to non-sense mediated decay.
- CV
- (coefficient of variation)
- TNF
- (Tumor Necrosis Factor alpha)
- SATURN
- (Splicing After Transfection of Unspliced RNA into Nucleus)