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Dynamic analysis of stochastic transcription cycles
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Harper, Claire V., Finkenstädt, Bärbel, Woodcock, Dan J., Friedrichsen, Sönke, Semprini, Sabrina, Ashall, Louise, Spiller, David G., Mullins, John J., Rand, D. A. (David A.), Davis, Julian R. E. and White, Michael R. H. (2011) Dynamic analysis of stochastic transcription cycles. PLos Biology, Vol.9 (No.4). doi:10.1371/journal.pbio.1000607 ISSN 1545-7885.
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WRAP_Rand_journal.pbio.1000607.pdf - Published Version - Requires a PDF viewer. Download (1943Kb) |
Official URL: http://dx.doi.org/10.1371/journal.pbio.1000607
Abstract
In individual mammalian cells the expression of some genes such as prolactin is highly variable over time and has been
suggested to occur in stochastic pulses. To investigate the origins of this behavior and to understand its functional
relevance, we quantitatively analyzed this variability using new mathematical tools that allowed us to reconstruct dynamic
transcription rates of different reporter genes controlled by identical promoters in the same living cell. Quantitative
microscopic analysis of two reporter genes, firefly luciferase and destabilized EGFP, was used to analyze the dynamics of
prolactin promoter-directed gene expression in living individual clonal and primary pituitary cells over periods of up to 25 h.
We quantified the time-dependence and cyclicity of the transcription pulses and estimated the length and variation of
active and inactive transcription phases. We showed an average cycle period of approximately 11 h and demonstrated that
while the measured time distribution of active phases agreed with commonly accepted models of transcription, the inactive
phases were differently distributed and showed strong memory, with a refractory period of transcriptional inactivation close
to 3 h. Cycles in transcription occurred at two distinct prolactin-promoter controlled reporter genes in the same individual
clonal or primary cells. However, the timing of the cycles was independent and out-of-phase. For the first time, we have
analyzed transcription dynamics from two equivalent loci in real-time in single cells. In unstimulated conditions, cells
showed independent transcription dynamics at each locus. A key result from these analyses was the evidence for a
minimum refractory period in the inactive-phase of transcription. The response to acute signals and the result of
manipulation of histone acetylation was consistent with the hypothesis that this refractory period corresponded to a phase
of chromatin remodeling which significantly increased the cyclicity. Stochastically timed bursts of transcription in an
apparently random subset of cells in a tissue may thus produce an overall coordinated but heterogeneous phenotype
capable of acute responses to stimuli.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QA Mathematics Q Science > QH Natural history > QH426 Genetics |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Statistics Faculty of Science, Engineering and Medicine > Research Centres > Warwick Systems Biology Centre |
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Library of Congress Subject Headings (LCSH): | Gene expression -- Mathematical models, Prolactin -- Mathematical models, Genetic transcription -- Mathematical models | ||||
Journal or Publication Title: | PLos Biology | ||||
Publisher: | Public Library of Science | ||||
ISSN: | 1545-7885 | ||||
Official Date: | 12 April 2011 | ||||
Dates: |
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Volume: | Vol.9 | ||||
Number: | No.4 | ||||
DOI: | 10.1371/journal.pbio.1000607 | ||||
Status: | Peer Reviewed | ||||
Access rights to Published version: | Open Access (Creative Commons) | ||||
Date of first compliant deposit: | 16 December 2015 | ||||
Date of first compliant Open Access: | 16 December 2015 | ||||
Funder: | Engineering and Physical Sciences Research Council (EPSRC), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Wellcome Trust (London, England), European Union (EU), British Heart Foundation, Manchester Academic Health Sciences Centre (MAHSC), National Institute for Health Research (Great Britain) (NIHR) | ||||
Grant number: | 67252 (WT), GR/S29256/01 (EPSRC), GR/S29256/01 (EPSRC), BB/F005938/1 (BBSRC), 005137 (EU), BBE0129651 (BBSRC) |
Data sourced from Thomson Reuters' Web of Knowledge
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