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Title: Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean

Abstract

Fundamental to biological decision-making is the ability to generate bimodal expression patterns where two alternate expression states simultaneously exist. Here in this study, we use a combination of single-cell analysis and mathematical modeling to examine the sources of bimodality in the transcriptional program controlling HIV’s fate decision between active replication and viral latency. We find that the HIV Tat protein manipulates the intrinsic toggling of HIV’s promoter, the LTR, to generate bimodal ON-OFF expression, and that transcriptional positive feedback from Tat shifts and expands the regime of LTR bimodality. This result holds for both minimal synthetic viral circuits and full-length virus. Strikingly, computational analysis indicates that the Tat circuit’s non-cooperative ‘non-latching’ feedback architecture is optimized to slow the promoter’s toggling and generate bimodality by stochastic extinction of Tat. In contrast to the standard Poisson model, theory and experiment show that non-latching positive feedback substantially dampens the inverse noise-mean relationship to maintain stochastic bimodality despite increasing mean-expression levels. Given the rapid evolution of HIV, the presence of a circuit optimized to robustly generate bimodal expression appears consistent with the hypothesis that HIV’s decision between active replication and latency provides a viral fitness advantage. More broadly, the results suggest that positive-feedback circuitsmore » may have evolved not only for signal amplification but also for robustly generating bimodality by decoupling expression fluctuations (noise) from mean expression levels.« less

Authors:
 [1];  [2];  [3];  [2]; ORCiD logo [4]; ORCiD logo [5]
  1. Rockefeller Univ., New York, NY (United States). Lab. of Virology and Infectious Disease; Gladstone Institutes (Virology and Immunology), San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States); 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 for Interdisciplinary Research and Graduate Education
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Gladstone Institutes (Virology and Immunology), San Francisco, CA (United States)
  4. 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 for Interdisciplinary Research and Graduate Education
  5. Gladstone Institutes (Virology and Immunology), San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States). Dept. of Biochemistry and Biophysics; Univ. of California, San Francisco, CA (United States). QB3: California Inst. of Quantitative Biosciences; Univ. of California, San Francisco, CA (United States). Dept. of Pharmaceutical Chemistry
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1407734
DOE Contract Number:
AC05-00OR22725
Resource Type:
Journal Article
Resource Relation:
Journal Name: PLoS biology (Online); Journal Volume: 15; Journal Issue: 10
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Razooky, Brandon S., Cao, Youfang, Hansen, Maike M. K., Perelson, Alan S., Simpson, Michael L., and Weinberger, Leor S. Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean. United States: N. p., 2017. Web. doi:10.1371/journal.pbio.2000841.
Razooky, Brandon S., Cao, Youfang, Hansen, Maike M. K., Perelson, Alan S., Simpson, Michael L., & Weinberger, Leor S. Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean. United States. doi:10.1371/journal.pbio.2000841.
Razooky, Brandon S., Cao, Youfang, Hansen, Maike M. K., Perelson, Alan S., Simpson, Michael L., and Weinberger, Leor S. Wed . "Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean". United States. doi:10.1371/journal.pbio.2000841. https://www.osti.gov/servlets/purl/1407734.
@article{osti_1407734,
title = {Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean},
author = {Razooky, Brandon S. and Cao, Youfang and Hansen, Maike M. K. and Perelson, Alan S. and Simpson, Michael L. and Weinberger, Leor S.},
abstractNote = {Fundamental to biological decision-making is the ability to generate bimodal expression patterns where two alternate expression states simultaneously exist. Here in this study, we use a combination of single-cell analysis and mathematical modeling to examine the sources of bimodality in the transcriptional program controlling HIV’s fate decision between active replication and viral latency. We find that the HIV Tat protein manipulates the intrinsic toggling of HIV’s promoter, the LTR, to generate bimodal ON-OFF expression, and that transcriptional positive feedback from Tat shifts and expands the regime of LTR bimodality. This result holds for both minimal synthetic viral circuits and full-length virus. Strikingly, computational analysis indicates that the Tat circuit’s non-cooperative ‘non-latching’ feedback architecture is optimized to slow the promoter’s toggling and generate bimodality by stochastic extinction of Tat. In contrast to the standard Poisson model, theory and experiment show that non-latching positive feedback substantially dampens the inverse noise-mean relationship to maintain stochastic bimodality despite increasing mean-expression levels. Given the rapid evolution of HIV, the presence of a circuit optimized to robustly generate bimodal expression appears consistent with the hypothesis that HIV’s decision between active replication and latency provides a viral fitness advantage. More broadly, the results suggest that positive-feedback circuits may have evolved not only for signal amplification but also for robustly generating bimodality by decoupling expression fluctuations (noise) from mean expression levels.},
doi = {10.1371/journal.pbio.2000841},
journal = {PLoS biology (Online)},
number = 10,
volume = 15,
place = {United States},
year = {Wed Oct 18 00:00:00 EDT 2017},
month = {Wed Oct 18 00:00:00 EDT 2017}
}
  • Bimodality is observed on the size of the heaviest released fragment for semi-peripheral heavy ion induced reactions in the intermediate energy domain. From lattice-gas calculations, this signal can sign a phase transition even if the system has not reached a complete equilibrium. It is shown from the data that it is correlated with other possible phase transition signals. The two bimodality solutions correspond to different excitation energies and to similar temperatures as expected if bimodality is due to a liquid-gas phase transition.
  • Highlights: • Y-encoded proto-oncoprotein TSPY amplifies its expression level via a positive feedback loop. • TSPY binds to the chromatin/DNA at exon 1 of TSPY gene. • TSPY enhances the gene expression in a TSPY exon 1 sequence dependent manner. • The conserved SET/NAP-domain is essential for TSPY transactivation. • Insights on probable mechanisms on TSPY exacerbation on cancer development in men. - Abstract: The testis-specific protein Y-encoded (TSPY) is a repetitive gene located on the gonadoblastoma region of the Y chromosome, and has been considered to be the putative gene for this oncogenic locus on the male-only chromosome. Itmore » is expressed in spermatogonial cells and spermatocytes in normal human testis, but abundantly in gonadoblastoma, testicular germ cell tumors and a variety of somatic cancers, including melanoma, hepatocellular carcinoma and prostate cancer. Various studies suggest that TSPY accelerates cell proliferation and growth, and promotes tumorigenesis. In this report, we show that TSPY could bind directly to the chromatin/DNA at exon 1 of its own gene, and greatly enhance the transcriptional activities of the endogenous gene in the LNCaP prostate cancer cells. Domain mapping analyses of TSPY have localized the critical and sufficient domain to the SET/NAP-domain. These results suggest that TSPY could efficiently amplify its expression and oncogenic functions through a positive feedback loop, and contribute to the overall tumorigenic processes when it is expressed in various human cancers.« less
  • We have designed and fabricated a low-noise dc superconducting quantum interference device (SQUID) magnetometer that is integrated on a 4{times}4 mm{sup 2} chip. The white flux noise of the magnetometer measured in a flux-locked-loop mode using simple, direct-coupled electronics with additional positive feedback (APF) is 6.4{times}10{sup {minus}7} {Phi}{sub 0}/{radical}Hz. The corresponding white flux density noise is 3.9 fT/{radical}Hz. The SQUID flux-to-voltage transfer function with APF is enhanced to 4.7 mV/{Phi}{sub 0} at the optimal working point, thereby significantly reducing the preamplifier contribution to the total noise. A maximum feedback field of 65 nT for frequencies up to 300 Hz andmore » a maximum slew rate of 120 {mu}T/s at 300 Hz have been attained using a two-pole integrator.« less
  • Three magnetometers based on dc superconducting quantum interference devices (SQUIDs) fabricated from YBa{sub 2}Cu{sub 3}O{sub 7{minus}{ital x}} have been operated in a magnetically shielded room using a flux-locked loop involving additional positive feedback with bias current reversal. Two of these devices, integrated multiloop dc SQUIDs with outer diameters of 7 mm, achieved white noise levels of 10 fT/{radical}Hz for bicrystal junctions and 30 fT/{radical}Hz for step-edge junctions. The third magnetometer involved a flux transformer with a 10{times}10 mm{sup 2} pickup coil connected to a 16-turn input coil which was inductively coupled to a bicrystal SQUID. This device achieved a whitemore » noise of 16.2 fT/{radical}Hz. High quality magnetocardiograms were obtained without signal averaging. {copyright} {ital 1996 American Institute of Physics.}« less