Diverse biological systems utilize gene-expression fluctuations (noise) to drive lineage-31 commitment decisions1-5. However, once a commitment is made, noise becomes detrimental 32 to reliable function6,7 and the mechanisms enabling post-commitment noise suppression are 33 unclear. We used time-lapse imaging and mathematical modeling, and found that, after a 34 noise-driven event, human immunodeficiency virus (HIV) strongly attenuated expression 35 noise through a non-transcriptional negative-feedback circuit. Feedback is established by 36 serial generation of RNAs from post-transcriptional splicing, creating a precursor-product 37 relationship where proteins generated from spliced mRNAs auto-deplete their own 38 precursor un-spliced mRNAs. Strikingly, precursor auto-depletion overcomes the 39 theoretical limits on conventional noise suppression, minimizing noise far better than 40 transcriptional auto-repression, and dramatically stabilizes commitment to the active-41 replication state. This auto-depletion feedback motif may efficiently suppress noise in 42 other systems ranging from detained introns to non-sense mediated decay.

A Feedback Motif that Breaks the Fundamental Limit on Noise Suppression to Stabilize Fate