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bioRxiv · 10.1101/141390

HIVs Feedback Circuit Breaks The Fundamental Limit On Noise Suppression To Stabilize Fate

Wen, W. Y.·Ingerman, E.·Hansen, M. M. K.·Razooky, B. S.·Dar, R. D.·Chin, C.·Simpson, M.·Weinberger, L. S.
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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. This auto-depletion feedback motif may efficiently suppress noise in other systems ranging from detained introns to non-sense mediated decay.

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Wen, W. Y., Ingerman, E., Hansen, M. M. K., Razooky, B. S., Dar, R. D., Chin, C., Simpson, M., Weinberger, L. S.. 2017-05-24. HIVs Feedback Circuit Breaks The Fundamental Limit On Noise Suppression To Stabilize Fate. https://doi.org/10.1101/141390

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