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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Feedback, Physiological*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • HIV-1 / genetics
  • HIV-1 / metabolism*
  • Humans
  • Jurkat Cells
  • Models, Biological
  • RNA Precursors / metabolism
  • RNA Processing, Post-Transcriptional
  • RNA Splicing
  • RNA, Messenger / metabolism*
  • Time-Lapse Imaging
  • tat Gene Products, Human Immunodeficiency Virus / genetics


  • RNA Precursors
  • RNA, Messenger
  • tat Gene Products, Human Immunodeficiency Virus
  • Green Fluorescent Proteins