期刊
CELL
卷 173, 期 7, 页码 1609-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.04.005
关键词
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资金
- Nikon Imaging Center, UCSF [S10 1S10OD017993-01A1]
- UCSF-Gladstone Center for AIDS Research flow core [P30 AI027763, S10 RR028962-01]
- Netherlands Organization of Scientific Research (NWO) through a Rubicon fellowship [019.153LW.028]
- Center for Nanophase Materials Sciences, a DOE Office of Science User Facility
- William and Ute Bowes Distinguished Professorship
- Pew Scholarship in the Biomedical Sciences
- Alfred P. Sloan Research Fellowship
- NIH [R01AI109593, P01AI090935, OD006677, OD17181]
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 autodeplete their own precursor unspliced mRNAs. Strikingly, this auto-depletion circuitry minimizes noise to stabilize HIV's commitment decision, and a noisesuppression 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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