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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. Lastly, 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.

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [3];  [3];  [4]
  1. Univ. of California, San Francisco, CA (United States). Gladstone-UCSF Center for Cell Circuitry, Gladstone Inst.
  2. Univ. of California, San Francisco, CA (United States). Gladstone-UCSF Center for Cell Circuitry, Gladstone Inst.; Univ. of California, San Diego, CA (United States). Bioinformatics and Systems Biology Graduate Program
  3. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Nanophase Materials Science (CNMS); Univ. of Tennessee, Knoxville, TN (United States). Bredesen Center
  4. Univ. of California, San Francisco, CA (United States). Gladstone-UCSF Center for Cell Circuitry, Gladstone Inst.; Univ. of California, San Francisco, CA (United States). Dept. of Pharmaceutical Chemistry; Univ. of California, San Francisco, CA (United States). Dept. of Biochemistry and Biophysics
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1439924
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 173; Journal ID: ISSN 0092-8674
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; stochastic noise; pulse chase; fate selection; feedback; post-transcriptional splicing; single-cell imaging; single-molecule imaging; HIVvirus; transcriptional fluctuations

Citation Formats

Hansen, Maike M. K., Wen, Winnie Y., Ingerman, Elena, Razooky, Brandon S., Thompson, Cassandra E., Dar, Roy D., Chin, Charles W., Simpson, Michael L., and Weinberger, Leor S. A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization. United States: N. p., 2018. Web. doi:10.1016/j.cell.2018.04.005.
Hansen, Maike M. K., Wen, Winnie Y., Ingerman, Elena, Razooky, Brandon S., Thompson, Cassandra E., Dar, Roy D., Chin, Charles W., Simpson, Michael L., & Weinberger, Leor S. A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization. United States. doi:10.1016/j.cell.2018.04.005.
Hansen, Maike M. K., Wen, Winnie Y., Ingerman, Elena, Razooky, Brandon S., Thompson, Cassandra E., Dar, Roy D., Chin, Charles W., Simpson, Michael L., and Weinberger, Leor S. Thu . "A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization". United States. doi:10.1016/j.cell.2018.04.005.
@article{osti_1439924,
title = {A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization},
author = {Hansen, Maike M. K. and Wen, Winnie Y. and Ingerman, Elena and Razooky, Brandon S. and Thompson, Cassandra E. and Dar, Roy D. and Chin, Charles W. and Simpson, Michael L. and Weinberger, Leor S.},
abstractNote = {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. Lastly, 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.},
doi = {10.1016/j.cell.2018.04.005},
journal = {Cell},
number = ,
volume = 173,
place = {United States},
year = {Thu May 10 00:00:00 EDT 2018},
month = {Thu May 10 00:00:00 EDT 2018}
}

Journal Article:
Free Publicly Available Full Text
This content will become publicly available on May 10, 2019
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