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 journalArticle

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 languageEnglish (US)
Pages (from-to)1609-1621.e15
JournalCell
Volume173
Issue number7
DOIs
StatePublished - 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

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Hansen, M. M. K., Wen, W. Y., Ingerman, E., Razooky, B. S., Thompson, C. E., Dar, R. D., Chin, C. W., Simpson, M. L., & Weinberger, L. S. (2018). A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization. Cell, 173(7), 1609-1621.e15. https://doi.org/10.1016/j.cell.2018.04.005