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

Maike M.K. Hansen, Winnie Y. Wen, Elena Ingerman, Brandon S. Razooky, Cassandra E. Thompson, Roy D. Dar, Charles W. Chin, Michael L. Simpson, Leor S. Weinberger

Research output: Contribution to journalArticlepeer-review


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 languageEnglish (US)
Pages (from-to)1609-1621.e15
Issue number7
StatePublished - Jun 14 2018


  • 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


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