PT - JOURNAL ARTICLE AU - Winnie Y. Wen AU - Elena Ingerman AU - Maike M. K. Hansen AU - Brandon S. Razooky AU - Roy D. Dar AU - Charles Chin AU - Michael Simpson AU - Leor S. Weinberger TI - A Feedback Motif that Breaks the Fundamental Limit on Noise Suppression to Stabilize Fate AID - 10.1101/141390 DP - 2017 Jan 01 TA - bioRxiv PG - 141390 4099 - http://biorxiv.org/content/early/2017/06/09/141390.short 4100 - http://biorxiv.org/content/early/2017/06/09/141390.full AB - 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. This auto-depletion feedback motif may efficiently suppress noise in other systems ranging from detained introns to non-sense mediated decay.