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Cell. 2018 Jun 14;173(7):1609-1621.e15. doi: 10.1016/j.cell.2018.04.005. Epub 2018 May 10.

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

Author information

1
Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA.
2
Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
3
Center for Nanophase Materials Science, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA; The Bredesen Center, University of Tennessee, Knoxville, TN 37996, USA.
4
Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA. Electronic address: leor.weinberger@gladstone.ucsf.edu.

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.

KEYWORDS:

HIV; fate selection; feedback; post-transcriptional splicing; pulse chase; single-cell imaging; single-molecule imaging; stochastic noise; transcriptional fluctuations; virus

PMID:
29754821
PMCID:
PMC6044448
[Available on 2019-06-14]
DOI:
10.1016/j.cell.2018.04.005

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