Quantifying Stochastic Noise in Cultured Circadian Reporter Cells
Abstract
Stochastic noise at the cellular level has been shown to play a fundamental role in circadian oscillations, influencing how groups of cells entrain to external cues and likely serving as the mechanism by which cell-autonomous rhythms are generated. Despite this importance, few studies have investigated how clock perturbations affect stochastic noise—even as increasing numbers of high-throughput screens categorize how gene knockdowns or small molecules can change clock period and amplitude. This absence is likely due to the difficulty associated with measuring cell-autonomous stochastic noise directly, which currently requires the careful collection and processing of single-cell data. In this study, we show that the damping rate of population-level bioluminescence recordings can serve as an accurate measure of overall stochastic noise, and one that can be applied to future and existing high-throughput circadian screens. Using cell-autonomous fibroblast data, we first show directly that higher noise at the single-cell results in faster damping at the population level. Next, we show that the damping rate of cultured cells can be changed in a dose-dependent fashion by small molecule modulators, and confirm that such a change can be explained by single-cell noise using a mathematical model. We further demonstrate the insights that can be gainedmore »
- Authors:
-
- Univ. of California, Santa Barbara, CA (United States). Dept. of Chemical Engineering; National Renewable Energy Lab. (NREL), Golden, CO (United States). Biosciences Center
- Univ. of California, Santa Barbara, CA (United States). Dept. of Chemical Engineering; Harvard Univ., Cambridge, MA (United States). Paulson School of Engineering and Applied Sciences
- Publication Date:
- Research Org.:
- National Renewable Energy Laboratory (NREL), Golden, CO (United States)
- Sponsoring Org.:
- National Institutes of Health/National Institute of General Medical Sciences; US Army Research Office (ARO); USDOE
- OSTI Identifier:
- 1235423
- Alternate Identifier(s):
- OSTI ID: 1235424
- Report Number(s):
- NREL/JA-2700-65654
Journal ID: ISSN 1553-734X
- Grant/Contract Number:
- AC36-08GO28308
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS Computational Biology
- Additional Journal Information:
- Journal Volume: 11; Journal Issue: 11; Journal ID: ISSN 1553-734X
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; circadian oscillators; genetic oscillators; circadian rhythms; bioluminescence; small molecules; small interfering RNAs; chronobiology; sine waves
Citation Formats
John, Peter C., and Doyle, III, Francis J. Quantifying Stochastic Noise in Cultured Circadian Reporter Cells. United States: N. p., 2015.
Web. doi:10.1371/journal.pcbi.1004451.
John, Peter C., & Doyle, III, Francis J. Quantifying Stochastic Noise in Cultured Circadian Reporter Cells. United States. https://doi.org/10.1371/journal.pcbi.1004451
John, Peter C., and Doyle, III, Francis J. Fri .
"Quantifying Stochastic Noise in Cultured Circadian Reporter Cells". United States. https://doi.org/10.1371/journal.pcbi.1004451. https://www.osti.gov/servlets/purl/1235423.
@article{osti_1235423,
title = {Quantifying Stochastic Noise in Cultured Circadian Reporter Cells},
author = {John, Peter C. and Doyle, III, Francis J.},
abstractNote = {Stochastic noise at the cellular level has been shown to play a fundamental role in circadian oscillations, influencing how groups of cells entrain to external cues and likely serving as the mechanism by which cell-autonomous rhythms are generated. Despite this importance, few studies have investigated how clock perturbations affect stochastic noise—even as increasing numbers of high-throughput screens categorize how gene knockdowns or small molecules can change clock period and amplitude. This absence is likely due to the difficulty associated with measuring cell-autonomous stochastic noise directly, which currently requires the careful collection and processing of single-cell data. In this study, we show that the damping rate of population-level bioluminescence recordings can serve as an accurate measure of overall stochastic noise, and one that can be applied to future and existing high-throughput circadian screens. Using cell-autonomous fibroblast data, we first show directly that higher noise at the single-cell results in faster damping at the population level. Next, we show that the damping rate of cultured cells can be changed in a dose-dependent fashion by small molecule modulators, and confirm that such a change can be explained by single-cell noise using a mathematical model. We further demonstrate the insights that can be gained by applying our method to a genome-wide siRNA screen, revealing that stochastic noise is altered independently from period, amplitude, and phase. Finally, we hypothesize that the unperturbed clock is highly optimized for robust rhythms, as very few gene perturbations are capable of simultaneously increasing amplitude and lowering stochastic noise. As a result, this study demonstrates the importance of considering the effect of circadian perturbations on stochastic noise, particularly with regard to the development of small-molecule circadian therapeutics.},
doi = {10.1371/journal.pcbi.1004451},
journal = {PLoS Computational Biology},
number = 11,
volume = 11,
place = {United States},
year = {Fri Nov 20 00:00:00 EST 2015},
month = {Fri Nov 20 00:00:00 EST 2015}
}
Web of Science
Works referenced in this record:
A Genome-wide RNAi Screen for Modifiers of the Circadian Clock in Human Cells
journal, October 2009
- Zhang, Eric E.; Liu, Andrew C.; Hirota, Tsuyoshi
- Cell, Vol. 139, Issue 1
Circadian Rhythms of PER2::LUC in Individual Primary Mouse Hepatocytes and Cultures
journal, February 2014
- Guenthner, Casey J.; Luitje, Martha E.; Pyle, Lorna A.
- PLoS ONE, Vol. 9, Issue 2
Stochastic Gene Expression in a Single Cell
journal, August 2002
- Elowitz, M. B.
- Science, Vol. 297, Issue 5584
StochKit2: software for discrete stochastic simulation of biochemical systems with events
journal, July 2011
- Sanft, K. R.; Wu, S.; Roh, M.
- Bioinformatics, Vol. 27, Issue 17
Small molecule modifiers of circadian clocks
journal, November 2012
- Chen, Zheng; Yoo, Seung-Hee; Takahashi, Joseph S.
- Cellular and Molecular Life Sciences, Vol. 70, Issue 16
Bioluminescence Imaging of Individual Fibroblasts Reveals Persistent, Independently Phased Circadian Rhythms of Clock Gene Expression
journal, December 2004
- Welsh, David K.; Yoo, Seung-Hee; Liu, Andrew C.
- Current Biology, Vol. 14, Issue 24
Persistent Cell-Autonomous Circadian Oscillations in Fibroblasts Revealed by Six-Week Single-Cell Imaging of PER2::LUC Bioluminescence
journal, March 2012
- Leise, Tanya L.; Wang, Connie W.; Gitis, Paula J.
- PLoS ONE, Vol. 7, Issue 3
Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior
journal, April 1994
- Vitaterna, M.; King, D.; Chang, A.
- Science, Vol. 264, Issue 5159
Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes
journal, June 2010
- Marcheva, Biliana; Ramsey, Kathryn Moynihan; Buhr, Ethan D.
- Nature, Vol. 466, Issue 7306
Circadian Gene Expression in Individual Fibroblasts
journal, November 2004
- Nagoshi, Emi; Saini, Camille; Bauer, Christoph
- Cell, Vol. 119, Issue 5
Matrix pencil method for estimating parameters of exponentially damped/undamped sinusoids in noise
journal, May 1990
- Hua, Y.; Sarkar, T. K.
- IEEE Transactions on Acoustics, Speech, and Signal Processing, Vol. 38, Issue 5
Design principles of biochemical oscillators
journal, October 2008
- Novák, Béla; Tyson, John J.
- Nature Reviews Molecular Cell Biology, Vol. 9, Issue 12
Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet
journal, June 2012
- Hatori, Megumi; Vollmers, Christopher; Zarrinpar, Amir
- Cell Metabolism, Vol. 15, Issue 6
Quantification of Circadian Rhythms in Single Cells
journal, November 2009
- Westermark, Pål O.; Welsh, David K.; Okamura, Hitoshi
- PLoS Computational Biology, Vol. 5, Issue 11
RNAi Microarray Analysis in Cultured Mammalian Cells
journal, October 2003
- Mousses, S.
- Genome Research, Vol. 13, Issue 10
Fibroblast PER2 Circadian Rhythmicity Depends on Cell Density
journal, June 2013
- Noguchi, Takako; Wang, Lexie L.; Welsh, David K.
- Journal of Biological Rhythms, Vol. 28, Issue 3
Identification of Small Molecule Activators of Cryptochrome
journal, July 2012
- Hirota, T.; Lee, J. W.; St. John, P. C.
- Science, Vol. 337, Issue 6098
Bayesian statistical analysis of circadian oscillations in fibroblasts
journal, December 2012
- Cohen, Andrew L.; Leise, Tanya L.; Welsh, David K.
- Journal of Theoretical Biology, Vol. 314
Neurons and networks in daily rhythms
journal, October 2007
- Herzog, Erik D.
- Nature Reviews Neuroscience, Vol. 8, Issue 10
System-level identification of transcriptional circuits underlying mammalian circadian clocks
journal, January 2005
- Ueda, Hiroki R.; Hayashi, Satoko; Chen, Wenbin
- Nature Genetics, Vol. 37, Issue 2
Circadian gene expression in mammalian fibroblasts revealed by real-time luminescence reporting: Temperature compensation and damping
journal, December 2003
- Izumo, M.; Johnson, C. H.; Yamazaki, S.
- Proceedings of the National Academy of Sciences, Vol. 100, Issue 26
A neuropeptide speeds circadian entrainment by reducing intercellular synchrony
journal, October 2013
- An, S.; Harang, R.; Meeker, K.
- Proceedings of the National Academy of Sciences, Vol. 110, Issue 46
Circadian clocks limited by noise
journal, January 2000
- Barkai, Naama; Leibler, Stanislas
- Nature, Vol. 403, Issue 6767
Statistical methods for analysis of high-throughput RNA interference screens
journal, July 2009
- Birmingham, Amanda; Selfors, Laura M.; Forster, Thorsten
- Nature Methods, Vol. 6, Issue 8
Amplitude Metrics for Cellular Circadian Bioluminescence Reporters
journal, December 2014
- St. John, Peter C.; Taylor, Stephanie R.; Abel, John H.
- Biophysical Journal, Vol. 107, Issue 11
Synchrony and mutual stimulation of yeast cells during fast glycolytic oscillations
journal, October 1992
- Aon, M. A.; Cortassa, S.; Westerhoff, H. V.
- Journal of General Microbiology, Vol. 138, Issue 10
Stochastic Phase Oscillators and Circadian Bioluminescence Recordings
journal, January 2007
- Rougemont, J.; Naef, F.
- Cold Spring Harbor Symposia on Quantitative Biology, Vol. 72, Issue 1
Temporal Precision in the Mammalian Circadian System: A Reliable Clock from Less Reliable Neurons
journal, February 2004
- Herzog, Erik D.; Aton, Sara J.; Numano, Rika
- Journal of Biological Rhythms, Vol. 19, Issue 1
Wavelet-Based Time Series Analysis of Circadian Rhythms
journal, September 2011
- Leise, Tanya L.; Harrington, Mary E.
- Journal of Biological Rhythms, Vol. 26, Issue 5
Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock
journal, January 2014
- St. John, Peter C.; Hirota, Tsuyoshi; Kay, Steve A.
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 5
A Serum Shock Induces Circadian Gene Expression in Mammalian Tissue Culture Cells
journal, June 1998
- Balsalobre, Aurélio; Damiola, Francesca; Schibler, Ueli
- Cell, Vol. 93, Issue 6
Oscillations in NF- B Signaling Control the Dynamics of Gene Expression
journal, October 2004
- Nelson, D. E.
- Science, Vol. 306, Issue 5696
Dynamical signatures of cellular fluctuations and oscillator stability in peripheral circadian clocks
journal, January 2007
- Rougemont, Jacques; Naef, Felix
- Molecular Systems Biology, Vol. 3, Issue 1
On Adjusting the Hodrick-Prescott Filter for the Frequency of Observations
journal, May 2002
- Ravn, Morten O.; Uhlig, Harald
- Review of Economics and Statistics, Vol. 84, Issue 2
Frequency and Damping Estimation Methods - An Overview
journal, January 2011
- Zieliński, Tomasz; Duda, Krzysztof
- Metrology and Measurement Systems, Vol. 18, Issue 4
Small molecule modifiers of circadian clocks
journal, November 2012
- Chen, Zheng; Yoo, Seung-Hee; Takahashi, Joseph S.
- Cellular and Molecular Life Sciences, Vol. 70, Issue 16
Amplitude Metrics for Cellular Circadian Bioluminescence Reporters
journal, December 2014
- St. John, Peter C.; Taylor, Stephanie R.; Abel, John H.
- Biophysical Journal, Vol. 107, Issue 11
Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet
journal, June 2012
- Hatori, Megumi; Vollmers, Christopher; Zarrinpar, Amir
- Cell Metabolism, Vol. 15, Issue 6
Bioluminescence Imaging of Individual Fibroblasts Reveals Persistent, Independently Phased Circadian Rhythms of Clock Gene Expression
journal, December 2004
- Welsh, David K.; Yoo, Seung-Hee; Liu, Andrew C.
- Current Biology, Vol. 14, Issue 24
Bayesian statistical analysis of circadian oscillations in fibroblasts
journal, December 2012
- Cohen, Andrew L.; Leise, Tanya L.; Welsh, David K.
- Journal of Theoretical Biology, Vol. 314
Why the Rat-1 Fibroblast Should Replace the SCN as the In Vitro Model of Choice
journal, June 1998
- Rosbash, Michael
- Cell, Vol. 93, Issue 6
Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes
journal, June 2010
- Marcheva, Biliana; Ramsey, Kathryn Moynihan; Buhr, Ethan D.
- Nature, Vol. 466, Issue 7306
Design principles of biochemical oscillators
journal, October 2008
- Novák, Béla; Tyson, John J.
- Nature Reviews Molecular Cell Biology, Vol. 9, Issue 12
Structural basis of BAK activation in mitochondrial apoptosis initiation
journal, January 2022
- Singh, Geetika; Guibao, Cristina D.; Seetharaman, Jayaraman
- Nature Communications, Vol. 13, Issue 1
Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock
journal, January 2014
- St. John, Peter C.; Hirota, Tsuyoshi; Kay, Steve A.
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 5
Circadian gene expression in mammalian fibroblasts revealed by real-time luminescence reporting: Temperature compensation and damping
journal, December 2003
- Izumo, M.; Johnson, C. H.; Yamazaki, S.
- Proceedings of the National Academy of Sciences, Vol. 100, Issue 26
RNAi Microarray Analysis in Cultured Mammalian Cells
journal, October 2003
- Mousses, S.
- Genome Research, Vol. 13, Issue 10
Stochastic Phase Oscillators and Circadian Bioluminescence Recordings
journal, January 2007
- Rougemont, J.; Naef, F.
- Cold Spring Harbor Symposia on Quantitative Biology, Vol. 72, Issue 1
Stochastic Gene Expression in a Single Cell
journal, August 2002
- Elowitz, M. B.
- Science, Vol. 297, Issue 5584
Identification of Small Molecule Activators of Cryptochrome
journal, July 2012
- Hirota, T.; Lee, J. W.; St. John, P. C.
- Science, Vol. 337, Issue 6098
Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior
journal, April 1994
- Vitaterna, M.; King, D.; Chang, A.
- Science, Vol. 264, Issue 5159
Temporal Precision in the Mammalian Circadian System: A Reliable Clock from Less Reliable Neurons
journal, February 2004
- Herzog, Erik D.; Aton, Sara J.; Numano, Rika
- Journal of Biological Rhythms, Vol. 19, Issue 1
Wavelet-Based Time Series Analysis of Circadian Rhythms
journal, September 2011
- Leise, Tanya L.; Harrington, Mary E.
- Journal of Biological Rhythms, Vol. 26, Issue 5
Fibroblast PER2 Circadian Rhythmicity Depends on Cell Density
journal, June 2013
- Noguchi, Takako; Wang, Lexie L.; Welsh, David K.
- Journal of Biological Rhythms, Vol. 28, Issue 3
Quantification of Circadian Rhythms in Single Cells
journal, November 2009
- Westermark, Pål O.; Welsh, David K.; Okamura, Hitoshi
- PLoS Computational Biology, Vol. 5, Issue 11
Persistent Cell-Autonomous Circadian Oscillations in Fibroblasts Revealed by Six-Week Single-Cell Imaging of PER2::LUC Bioluminescence
journal, March 2012
- Leise, Tanya L.; Wang, Connie W.; Gitis, Paula J.
- PLoS ONE, Vol. 7, Issue 3
Circadian Rhythms of PER2::LUC in Individual Primary Mouse Hepatocytes and Cultures
journal, February 2014
- Guenthner, Casey J.; Luitje, Martha E.; Pyle, Lorna A.
- PLoS ONE, Vol. 9, Issue 2
Works referencing / citing this record:
The choroid plexus is an important circadian clock component
journal, March 2018
- Myung, Jihwan; Schmal, Christoph; Hong, Sungho
- Nature Communications, Vol. 9, Issue 1
Moran’s I quantifies spatio-temporal pattern formation in neural imaging data
journal, May 2017
- Schmal, Christoph; Myung, Jihwan; Herzel, Hanspeter
- Bioinformatics, Vol. 33, Issue 19
The choroid plexus is an important circadian clock component
journal, March 2018
- Myung, Jihwan; Schmal, Christoph; Hong, Sungho
- Nature Communications, Vol. 9, Issue 1
Moran’s I quantifies spatio-temporal pattern formation in neural imaging data
journal, May 2017
- Schmal, Christoph; Myung, Jihwan; Herzel, Hanspeter
- Bioinformatics, Vol. 33, Issue 19