A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization.

Cell
Maike M K HansenLeor S Weinberger

Abstract

Diverse biological systems utilize fluctuations ("noise") in gene expression to drive lineage-commitment decisions. However, once a commitment is made, noise becomes detrimental to reliable function, and the mechanisms enabling post-commitment noise suppression are unclear. Here, we find that architectural constraints on noise suppression are overcome to stabilize fate commitment. Using single-molecule and time-lapse imaging, we find that-after a noise-driven event-human immunodeficiency virus (HIV) strongly attenuates expression noise through a non-transcriptional negative-feedback circuit. Feedback is established through a serial cascade of post-transcriptional splicing, whereby proteins generated from spliced mRNAs auto-deplete their own precursor unspliced mRNAs. Strikingly, this auto-depletion circuitry minimizes noise to stabilize HIV's commitment decision, and a noise-suppression molecule promotes stabilization. This feedback mechanism for noise suppression suggests a functional role for delayed splicing in other systems and may represent a generalizable architecture of diverse homeostatic signaling circuits.

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Citations

Jan 31, 2020·PLoS Pathogens·Birgitta LindqvistJ Peter Svensson
Jun 22, 2019·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Maike M K Hansen, Leor S Weinberger
Dec 25, 2019·Proceedings of the National Academy of Sciences of the United States of America·Efrat M CohenOren Kobiler
May 3, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yan LiJoseph S Takahashi
Feb 12, 2020·Molecular Systems Biology·Robert Foreman, Roy Wollman
Jul 8, 2020·Proceedings of the National Academy of Sciences of the United States of America·Sonali ChaturvediLeor S Weinberger
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Nov 26, 2019·Cell Host & Microbe·Jason M HatayeRichard A Koup
Apr 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Yiyang LuRoy D Dar

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