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 David 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

Fingerprint

Noise
Stabilization
Feedback
Molecules
Networks (circuits)
RNA Precursors
Alternative Splicing
Biological systems
Viruses
Gene expression
Imaging techniques
Messenger RNA
Time-Lapse Imaging
HIV
Protein Splicing
Proteins
Gene Expression

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)

Cite this

Hansen, M. M. K., Wen, W. Y., Ingerman, E., Razooky, B. S., Thompson, C. E., Dar, R. D., ... 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

A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization. / Hansen, Maike M.K.; Wen, Winnie Y.; Ingerman, Elena; Razooky, Brandon S.; Thompson, Cassandra E.; Dar, Roy David; Chin, Charles W.; Simpson, Michael L.; Weinberger, Leor S.

In: Cell, Vol. 173, No. 7, 14.06.2018, p. 1609-1621.e15.

Research output: Contribution to journalArticle

Hansen, MMK, Wen, WY, Ingerman, E, Razooky, BS, Thompson, CE, Dar, RD, Chin, CW, Simpson, ML & Weinberger, LS 2018, 'A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization', Cell, vol. 173, no. 7, pp. 1609-1621.e15. https://doi.org/10.1016/j.cell.2018.04.005
Hansen MMK, Wen WY, Ingerman E, Razooky BS, Thompson CE, Dar RD et al. A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization. Cell. 2018 Jun 14;173(7):1609-1621.e15. https://doi.org/10.1016/j.cell.2018.04.005
Hansen, Maike M.K. ; Wen, Winnie Y. ; Ingerman, Elena ; Razooky, Brandon S. ; Thompson, Cassandra E. ; Dar, Roy David ; Chin, Charles W. ; Simpson, Michael L. ; Weinberger, Leor S. / A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization. In: Cell. 2018 ; Vol. 173, No. 7. pp. 1609-1621.e15.
@article{a1c16c9648114989bdde9bdc75389613,
title = "A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization",
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.",
keywords = "HIV, fate selection, feedback, post-transcriptional splicing, pulse chase, single-cell imaging, single-molecule imaging, stochastic noise, transcriptional fluctuations, virus",
author = "Hansen, {Maike M.K.} and Wen, {Winnie Y.} and Elena Ingerman and Razooky, {Brandon S.} and Thompson, {Cassandra E.} and Dar, {Roy David} and Chin, {Charles W.} and Simpson, {Michael L.} and Weinberger, {Leor S.}",
year = "2018",
month = "6",
day = "14",
doi = "10.1016/j.cell.2018.04.005",
language = "English (US)",
volume = "173",
pages = "1609--1621.e15",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "7",

}

TY - JOUR

T1 - A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization

AU - Hansen, Maike M.K.

AU - Wen, Winnie Y.

AU - Ingerman, Elena

AU - Razooky, Brandon S.

AU - Thompson, Cassandra E.

AU - Dar, Roy David

AU - Chin, Charles W.

AU - Simpson, Michael L.

AU - Weinberger, Leor S.

PY - 2018/6/14

Y1 - 2018/6/14

N2 - 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.

AB - 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.

KW - HIV

KW - fate selection

KW - feedback

KW - post-transcriptional splicing

KW - pulse chase

KW - single-cell imaging

KW - single-molecule imaging

KW - stochastic noise

KW - transcriptional fluctuations

KW - virus

UR - http://www.scopus.com/inward/record.url?scp=85046690851&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046690851&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.04.005

DO - 10.1016/j.cell.2018.04.005

M3 - Article

C2 - 29754821

AN - SCOPUS:85046690851

VL - 173

SP - 1609-1621.e15

JO - Cell

JF - Cell

SN - 0092-8674

IS - 7

ER -