Macromolecular Crowding Regulates the Gene Expression Profile by Limiting Diffusion

Golkaram, Mahdi; Hellander, Stefan; Drawert, Brian; Petzold, Linda R.

doi:10.1371/journal.pcbi.1005122

Title: Macromolecular Crowding Regulates the Gene Expression Profile by Limiting Diffusion

Journal Article · Mon Nov 28 00:00:00 EST 2016 · PLoS Computational Biology (Online)

DOI:https://doi.org/10.1371/journal.pcbi.1005122· OSTI ID:1345287

Golkaram, Mahdi ^[1]; Hellander, Stefan ^[2]; Drawert, Brian ^[2]; Petzold, Linda R. ^[3]

Univ. of California, Santa Barbara, CA (United States). Dept. of Mechanical Engineering
Univ. of California, Santa Barbara, CA (United States). Dept. of Computer Science
Univ. of California, Santa Barbara, CA (United States). Dept. of Mechanical Engineering and Dept. of Computer Science

We seek to elucidate the role of macromolecular crowding in transcription and translation. It is well known that stochasticity in gene expression can lead to differential gene expression and heterogeneity in a cell population. Recent experimental observations by Tan et al. have improved our understanding of the functional role of macromolecular crowding. It can be inferred from their observations that macromolecular crowding can lead to robustness in gene expression, resulting in a more homogeneous cell population. We introduce a spatial stochastic model to provide insight into this process. Our results show that macromolecular crowding reduces noise (as measured by the kurtosis of the mRNA distribution) in a cell population by limiting the diffusion of transcription factors (i.e. removing the unstable intermediate states), and that crowding by large molecules reduces noise more efficiently than crowding by small molecules. Finally, our simulation results provide evidence that the local variation in chromatin density as well as the total volume exclusion of the chromatin in the nucleus can induce a homogenous cell population

View Journal Article

Cite

Export

Save

Research Organization:: Univ. of California, Santa Barbara, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Science Foundation (NSF); US Army Research Office (ARO)

Grant/Contract Number:: SC0008975; DMS-1001012; W911NF-09-0001; R01-EB014877; R01-GM113241

OSTI ID:: 1345287

Alternate ID(s):: OSTI ID: 1423941

Journal Information:: PLoS Computational Biology (Online), Journal Name: PLoS Computational Biology (Online) Vol. 12 Journal Issue: 11; ISSN 1553-7358

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 26 works

Citation information provided by
Web of Science

References (67)

Probing Transcription Factor Dynamics at the Single-Molecule Level in a Living Cell Elf, J.; Li, G. -W.; Xie, X. S. Science, Vol. 316, Issue 5828 https://doi.org/10.1126/science.1141967	journal	May 2007
Importance of Crowding in Signaling, Genetic, and Metabolic Networks ten Wolde, Pieter Rein; Mugler, Andrew International Review of Cell and Molecular Biology https://doi.org/10.1016/B978-0-12-800046-5.00012-6	book	January 2014
Macromolecular Crowding Improves Polymer Encapsulation within Giant Lipid Vesicles Dominak, Lisa M.; Keating, Christine D. Langmuir, Vol. 24, Issue 23 https://doi.org/10.1021/la8028403	journal	December 2008
Stochastic Gene Expression in a Single Cell Elowitz, M. B. Science, Vol. 297, Issue 5584 https://doi.org/10.1126/science.1070919	journal	August 2002
Mechanism of Transcriptional Bursting in Bacteria Chong, Shasha; Chen, Chongyi; Ge, Hao Cell, Vol. 158, Issue 2 https://doi.org/10.1016/j.cell.2014.05.038	journal	July 2014
Experimental evidence for the influence of molecular crowding on nuclear architecture Richter, K.; Nessling, M.; Lichter, P. Journal of Cell Science, Vol. 120, Issue 9 https://doi.org/10.1242/jcs.03440	journal	April 2007
Transcription Dynamics Hager, Gordon L.; McNally, James G.; Misteli, Tom Molecular Cell, Vol. 35, Issue 6 https://doi.org/10.1016/j.molcel.2009.09.005	journal	September 2009
Molecular crowding shapes gene expression in synthetic cellular nanosystems Tan, Cheemeng; Saurabh, Saumya; Bruchez, Marcel P. Nature Nanotechnology, Vol. 8, Issue 8 https://doi.org/10.1038/nnano.2013.132	journal	July 2013
Intracellular crowding defines the mode and sequence of substrate uptake by Escherichia coli and constrains its metabolic activity Beg, Q. K.; Vazquez, A.; Ernst, J. Proceedings of the National Academy of Sciences, Vol. 104, Issue 31 https://doi.org/10.1073/pnas.0609845104	journal	July 2007
MOLNs: A Cloud Platform for Interactive, Reproducible, and Scalable Spatial Stochastic Computational Experiments in Systems Biology Using PyURDME Drawert, Brian; Trogdon, Michael; Toor, Salman SIAM Journal on Scientific Computing, Vol. 38, Issue 3 https://doi.org/10.1137/15M1014784	journal	January 2016
Spatial effects on the speed and reliability of protein–DNA search Wunderlich, Zeba; Mirny, Leonid A. Nucleic Acids Research, Vol. 36, Issue 11 https://doi.org/10.1093/nar/gkn173	journal	May 2008
Electrostatics in biomolecular structure and dynamics Davis, Malcolm E.; McCammon, J. Andrew Chemical Reviews, Vol. 90, Issue 3 https://doi.org/10.1021/cr00101a005	journal	May 1990
Stochastic Simulation of Coupled Reaction–Diffusion Processes Stundzia, Audrius B.; Lumsden, Charles J. Journal of Computational Physics, Vol. 127, Issue 1 https://doi.org/10.1006/jcph.1996.0168	journal	August 1996
Elite and stochastic models for induced pluripotent stem cell generation Yamanaka, Shinya Nature, Vol. 460, Issue 7251 https://doi.org/10.1038/nature08180	journal	July 2009
Effect of Nanochannel Geometry on DNA Structure in the Presence of Macromolecular Crowding Agent Jones, Jeremy J.; van der Maarel, Johan R. C.; Doyle, Patrick S. Nano Letters, Vol. 11, Issue 11 https://doi.org/10.1021/nl203114f	journal	November 2011
Bursts and pulses: insights from single cell studies into transcriptional mechanisms Chubb, Jonathan R.; Liverpool, Tanniemola B. Current Opinion in Genetics & Development, Vol. 20, Issue 5 https://doi.org/10.1016/j.gde.2010.06.009	journal	October 2010
Control, exploitation and tolerance of intracellular noise Rao, Christopher V.; Wolf, Denise M.; Arkin, Adam P. Nature, Vol. 420, Issue 6912 https://doi.org/10.1038/nature01258	journal	November 2002
Facilitated Diffusion of DNA-Binding Proteins Klenin, Konstantin V.; Merlitz, Holger; Langowski, Jörg Physical Review Letters, Vol. 96, Issue 1 https://doi.org/10.1103/PhysRevLett.96.018104	journal	January 2006
Control of Stochasticity in Eukaryotic Gene Expression Raser, J. M. Science, Vol. 304, Issue 5678 https://doi.org/10.1126/science.1098641	journal	June 2004
Maintenance of Stable Heterochromatin Domains by Dynamic HP1 Binding Cheutin, T. Science, Vol. 299, Issue 5607 https://doi.org/10.1126/science.1078572	journal	January 2003
Tunability and Noise Dependence in Differentiation Dynamics Suel, G. M.; Kulkarni, R. P.; Dworkin, J. Science, Vol. 315, Issue 5819 https://doi.org/10.1126/science.1137455	journal	March 2007
Diffusion of Transcription Factors Can Drastically Enhance the Noise in Gene Expression van Zon, Jeroen S.; Morelli, Marco J.; Tǎnase-Nicola, Sorin Biophysical Journal, Vol. 91, Issue 12 https://doi.org/10.1529/biophysj.106.086157	journal	December 2006
From molecular noise to behavioural variability in a single bacterium Korobkova, Ekaterina; Emonet, Thierry; Vilar, Jose M. G. Nature, Vol. 428, Issue 6982 https://doi.org/10.1038/nature02404	journal	April 2004
Spatial Stochastic Dynamics Enable Robust Cell Polarization Lawson, Michael J.; Drawert, Brian; Khammash, Mustafa PLoS Computational Biology, Vol. 9, Issue 7 https://doi.org/10.1371/journal.pcbi.1003139	journal	July 2013
Macromolecular crowding: obvious but underappreciated Ellis, R. John Trends in Biochemical Sciences, Vol. 26, Issue 10 https://doi.org/10.1016/S0968-0004(01)01938-7	journal	October 2001
Stochasticity in gene expression: from theories to phenotypes Kærn, Mads; Elston, Timothy C.; Blake, William J. Nature Reviews Genetics, Vol. 6, Issue 6 https://doi.org/10.1038/nrg1615	journal	May 2005
Perspective: Stochastic algorithms for chemical kinetics Gillespie, Daniel T.; Hellander, Andreas; Petzold, Linda R. The Journal of Chemical Physics, Vol. 138, Issue 17 https://doi.org/10.1063/1.4801941	journal	May 2013
Tracer diffusion of globular proteins in concentrated protein solutions. Muramatsu, N.; Minton, A. P. Proceedings of the National Academy of Sciences, Vol. 85, Issue 9 https://doi.org/10.1073/pnas.85.9.2984	journal	May 1988
Subdiffraction Multicolor Imaging of the Nuclear Periphery with 3D Structured Illumination Microscopy Schermelleh, L.; Carlton, P. M.; Haase, S. Science, Vol. 320, Issue 5881 https://doi.org/10.1126/science.1156947	journal	June 2008
Graded and binary responses in stochastic gene expression Karmakar, Rajesh; Bose, Indrani Physical Biology, Vol. 1, Issue 4 https://doi.org/10.1088/1478-3967/1/4/001	journal	November 2004
Molecular finite-size effects in stochastic models of equilibrium chemical systems Cianci, Claudia; Smith, Stephen; Grima, Ramon The Journal of Chemical Physics, Vol. 144, Issue 8 https://doi.org/10.1063/1.4941583	journal	February 2016
Functional roles for noise in genetic circuits Eldar, Avigdor; Elowitz, Michael B. Nature, Vol. 467, Issue 7312 https://doi.org/10.1038/nature09326	journal	September 2010
Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease Feinberg, A. P.; Irizarry, R. A. Proceedings of the National Academy of Sciences, Vol. 107, Issue suppl_1 https://doi.org/10.1073/pnas.0906183107	journal	December 2009
Interconvertible Lac Repressor–DNA Loops Revealed by Single-Molecule Experiments Wong, Oi Kwan; Guthold, Martin; Erie, Dorothy A. PLoS Biology, Vol. 6, Issue 9 https://doi.org/10.1371/journal.pbio.0060232	journal	September 2008
Gene Expression Noise in Spatial Patterning: hunchback Promoter Structure Affects Noise Amplitude and Distribution in Drosophila Segmentation Holloway, David M.; Lopes, Francisco J. P.; da Fontoura Costa, Luciano PLoS Computational Biology, Vol. 7, Issue 2 https://doi.org/10.1371/journal.pcbi.1001069	journal	February 2011
Stochastic gene expression, disruption of tissue averaging effects and cancer as a disease of development Capp, Jean-Pascal BioEssays, Vol. 27, Issue 12 https://doi.org/10.1002/bies.20326	journal	January 2005
Fluctuations in transcription factor binding can explain the graded and binary responses observed in inducible gene expression Pirone, Jason R.; Elston, Timothy C. Journal of Theoretical Biology, Vol. 226, Issue 1 https://doi.org/10.1016/j.jtbi.2003.08.008	journal	January 2004
The effect of volume occupancy upon the thermodynamic activity of proteins: some biochemical consequences Minton, Allen P. Molecular and Cellular Biochemistry, Vol. 55, Issue 2 https://doi.org/10.1007/BF00673707	journal	January 1983
Intrinsic and extrinsic contributions to stochasticity in gene expression Swain, P. S.; Elowitz, M. B.; Siggia, E. D. Proceedings of the National Academy of Sciences, Vol. 99, Issue 20 https://doi.org/10.1073/pnas.162041399	journal	September 2002
Noise in Gene Expression: Origins, Consequences, and Control Raser, J. M. Science, Vol. 309, Issue 5743 https://doi.org/10.1126/science.1105891	journal	September 2005
Relevance and Limitations of Crowding, Fractal, and Polymer Models to Describe Nuclear Architecture Huet, Sébastien; Lavelle, Christophe; Ranchon, Hubert International Review of Cell and Molecular Biology https://doi.org/10.1016/B978-0-12-800046-5.00013-8	book	January 2014
Computational methods for diffusion-influenced biochemical reactions Dobrzyński, Maciej; Rodríguez, Jordi Vidal; Kaandorp, Jaap A. Bioinformatics, Vol. 23, Issue 15 https://doi.org/10.1093/bioinformatics/btm278	journal	May 2007
How a protein searches for its site on DNA: the mechanism of facilitated diffusion Mirny, Leonid; Slutsky, Michael; Wunderlich, Zeba Journal of Physics A: Mathematical and Theoretical, Vol. 42, Issue 43 https://doi.org/10.1088/1751-8113/42/43/434013	journal	October 2009
Effects of Macromolecular Crowding on Genetic Networks Morelli, Marco J.; Allen, Rosalind J.; Rein ten Wolde, Pieter Biophysical Journal, Vol. 101, Issue 12 https://doi.org/10.1016/j.bpj.2011.10.053	journal	December 2011
Analysis of the size dependence of macromolecular crowding shows that smaller is better Sharp, Kim A. Proceedings of the National Academy of Sciences, Vol. 112, Issue 26 https://doi.org/10.1073/pnas.1505396112	journal	June 2015
Amplifying the Macromolecular Crowding Effect Using Nanoparticles Zaki, Ahmed; Dave, Neeshma; Liu, Juewen Journal of the American Chemical Society, Vol. 134, Issue 1 https://doi.org/10.1021/ja207661z	journal	December 2011
Efficient stochastic simulation of reaction–diffusion processes via direct compilation Lis, Mieszko; Artyomov, Maxim N.; Devadas, Srinivas Bioinformatics, Vol. 25, Issue 17 https://doi.org/10.1093/bioinformatics/btp387	journal	July 2009
Chemical space and biology Dobson, Christopher M. Nature, Vol. 432, Issue 7019 https://doi.org/10.1038/nature03192	journal	December 2004
Lower bound on the precision of transcriptional regulation and why facilitated diffusion can reduce noise in gene expression Paijmans, Joris; ten Wolde, Pieter Rein Physical Review E, Vol. 90, Issue 3 https://doi.org/10.1103/PhysRevE.90.032708	journal	September 2014
Chromatin Motion Is Constrained by Association with Nuclear Compartments in Human Cells Chubb, Jonathan R.; Boyle, Shelagh; Perry, Paul Current Biology, Vol. 12, Issue 6 https://doi.org/10.1016/S0960-9822(02)00695-4	journal	March 2002
A Hydrodynamic Effect in the Rates of Diffusion-Controlled Reactions ¹ Friedman, Harold L. The Journal of Physical Chemistry, Vol. 70, Issue 12 https://doi.org/10.1021/j100884a031	journal	December 1966
The Influence of Macromolecular Crowding and Macromolecular Confinement on Biochemical Reactions in Physiological Media Minton, Allen P. Journal of Biological Chemistry, Vol. 276, Issue 14 https://doi.org/10.1074/jbc.R100005200	journal	February 2001
Noise Propagation in Gene Networks Pedraza, J. M. Science, Vol. 307, Issue 5717 https://doi.org/10.1126/science.1109090	journal	March 2005
On Estimation of a Probability Density Function and Mode Parzen, Emanuel The Annals of Mathematical Statistics, Vol. 33, Issue 3 https://doi.org/10.1214/aoms/1177704472	journal	September 1962
Increased cell-to-cell variation in gene expression in ageing mouse heart Bahar, Rumana; Hartmann, Claudia H.; Rodriguez, Karl A. Nature, Vol. 441, Issue 7096 https://doi.org/10.1038/nature04844	journal	June 2006
The promoter-search mechanism of Escherichia coli RNA polymerase is dominated by three-dimensional diffusion Wang, Feng; Redding, Sy; Finkelstein, Ilya J. Nature Structural & Molecular Biology, Vol. 20, Issue 2 https://doi.org/10.1038/nsmb.2472	journal	December 2012
Non-genetic cell-to-cell variability and the consequences for pharmacology Niepel, Mario; Spencer, Sabrina L.; Sorger, Peter K. Current Opinion in Chemical Biology, Vol. 13, Issue 5-6 https://doi.org/10.1016/j.cbpa.2009.09.015	journal	December 2009
The influence of volume exclusion by chromatin on the time required to find specific DNA binding sites by diffusion Isaacson, S. A.; McQueen, D. M.; Peskin, Charles S. Proceedings of the National Academy of Sciences, Vol. 108, Issue 9 https://doi.org/10.1073/pnas.1018821108	journal	February 2011
Stochastic switching as a survival strategy in fluctuating environments Acar, Murat; Mettetal, Jerome T.; van Oudenaarden, Alexander Nature Genetics, Vol. 40, Issue 4 https://doi.org/10.1038/ng.110	journal	March 2008
Modeling stochastic gene expression: Implications for haploinsufficiency Cook, D. L.; Gerber, A. N.; Tapscott, S. J. Proceedings of the National Academy of Sciences, Vol. 95, Issue 26 https://doi.org/10.1073/pnas.95.26.15641	journal	December 1998
Stochastic gene expression as a molecular switch for viral latency Singh, Abhyudai; Weinberger, Leor S. Current Opinion in Microbiology, Vol. 12, Issue 4 https://doi.org/10.1016/j.mib.2009.06.016	journal	August 2009
Effects of macromolecular crowding and DNA looping on gene regulation kinetics Li, Gene-Wei; Berg, Otto G.; Elf, Johan Nature Physics, Vol. 5, Issue 4 https://doi.org/10.1038/nphys1222	journal	March 2009
The effects of molecular noise and size control on variability in the budding yeast cell cycle Talia, Stefano Di; Skotheim, Jan M.; Bean, James M. Nature, Vol. 448, Issue 7156 https://doi.org/10.1038/nature06072	journal	August 2007
Noise in eukaryotic gene expression Blake, William J.; KÆrn, Mads; Cantor, Charles R. Nature, Vol. 422, Issue 6932 https://doi.org/10.1038/nature01546	journal	April 2003
Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis Spencer, Sabrina L.; Gaudet, Suzanne; Albeck, John G. Nature, Vol. 459, Issue 7245 https://doi.org/10.1038/nature08012	journal	April 2009
Linking Stochastic Dynamics to Population Distribution: An Analytical Framework of Gene Expression Friedman, Nir; Cai, Long; Xie, X. Sunney Physical Review Letters, Vol. 97, Issue 16 https://doi.org/10.1103/PhysRevLett.97.168302	journal	October 2006
Phenomenological scaling laws for ‘‘semidilute’’ macromolecule solutions from light scattering by optical probe particles Phillies, George D. J.; Ullmann, Gregory S.; Ullmann, Kathleen The Journal of Chemical Physics, Vol. 82, Issue 11 https://doi.org/10.1063/1.448969	journal	June 1985

Similar Records

A framework for discrete stochastic simulation on 3D moving boundary domains

Journal Article · Mon Nov 14 00:00:00 EST 2016 · Journal of Chemical Physics · OSTI ID:1345287

Drawert, Brian; Hellander, Stefan; Trogdon, Michael; +2 more

Stochastic Simulation Service: Bridging the Gap between the Computational Expert and the Biologist

Journal Article · Thu Dec 08 00:00:00 EST 2016 · PLoS Computational Biology (Online) · OSTI ID:1345287

Drawert, Brian; Hellander, Andreas; Bales, Ben; +14 more

Macromolecular Crowding Induces Spatial Correlations That Control Gene Expression Bursting Patterns

Journal Article · Tue Apr 24 00:00:00 EDT 2018 · ACS Synthetic Biology · OSTI ID:1345287

Norred, Sarah Elizabeth; Caveney, Patrick M.; Chauhan, Gaurav; +4 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Title: Macromolecular Crowding Regulates the Gene Expression Profile by Limiting Diffusion

Citation Formats

References (67)

Similar Records

Related Subjects