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. Noise helps drive fate decisions, and a mechanism rooted in alternative splicing allows cells to stop dithering and commit.
Original language | English (US) |
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Pages (from-to) | 1609-1621.e15 |
Journal | Cell |
Volume | 173 |
Issue number | 7 |
DOIs | |
State | Published - Jun 14 2018 |
Keywords
- HIV
- fate selection
- feedback
- post-transcriptional splicing
- pulse chase
- single-cell imaging
- single-molecule imaging
- stochastic noise
- transcriptional fluctuations
- virus
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology