Quantifying the contribution of chromatin dynamics to stochastic gene expression reveals long, locus-dependent periods b
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RESEARCH ARTICLE
Open Access
Quantifying the contribution of chromatin dynamics to stochastic gene expression reveals long, locus-dependent periods between transcriptional bursts José Viñuelas1†, Gaël Kaneko1,2†, Antoine Coulon3, Elodie Vallin1, Valérie Morin1, Camila Mejia-Pous1, Jean-Jacques Kupiec4, Guillaume Beslon2 and Olivier Gandrillon1*
Abstract Background: A number of studies have established that stochasticity in gene expression may play an important role in many biological phenomena. This therefore calls for further investigations to identify the molecular mechanisms at stake, in order to understand and manipulate cell-to-cell variability. In this work, we explored the role played by chromatin dynamics in the regulation of stochastic gene expression in higher eukaryotic cells. Results: For this purpose, we generated isogenic chicken-cell populations expressing a fluorescent reporter integrated in one copy per clone. Although the clones differed only in the genetic locus at which the reporter was inserted, they showed markedly different fluorescence distributions, revealing different levels of stochastic gene expression. Use of chromatin-modifying agents showed that direct manipulation of chromatin dynamics had a marked effect on the extent of stochastic gene expression. To better understand the molecular mechanism involved in these phenomena, we fitted these data to a two-state model describing the opening/closing process of the chromatin. We found that the differences between clones seemed to be due mainly to the duration of the closed state, and that the agents we used mainly seem to act on the opening probability. Conclusions: In this study, we report biological experiments combined with computational modeling, highlighting the importance of chromatin dynamics in stochastic gene expression. This work sheds a new light on the mechanisms of gene expression in higher eukaryotic cells, and argues in favor of relatively slow dynamics with long (hours to days) periods of quiet state. Keywords: Chromatin dynamics, expression noise, gene regulation, stochastic model
Background Although the importance of stochasticity in gene expression has been anticipated more than three decades ago [1-3], the existence of a strong stochastic component in gene expression has only recently been experimentally demonstrated, showing that, despite constant environmental conditions, isogenic cells do show significant fluctuations in their gene-expression levels [4-10]. Moreover, * Correspondence: [email protected] † Contributed equally 1 Université de Lyon, Université Lyon 1, Centre de Génétique et de Physiologie Moléculaire et Cellulaire (CGPhiMC), CNRS UMR5534, F-69622 Lyon, France Full list of author information is available at the end of the article
regulated stochasticity, and its resulting phenotypic diversity, has been shown to be involved in several biological processes [11], including cell differentiation [12,13], development [14,15], virus decision-making [12,16], and bacterial survival during environ
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