Dynamics of epigenetic regulation at the single-cell level

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Science  12 Feb 2016:
Vol. 351, Issue 6274, pp. 720-724
DOI: 10.1126/science.aab2956

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Quantitative analysis of epigenetic memory

To explore quantitative and dynamic properties of transcriptional regulation by epigenetic modifications, Bintu et al. monitored a transcriptional reporter gene carried on a human artificial chromosome in Chinese hamster ovary cells (see the Perspective by Keung and Khalil). They measured effects of DNA methylation and histone modifications by methylation or deacetylation in single cells using time-lapse microscopy. Silencing was an all-or-none, stochastic event, so graded adjustments to transcription occurred from changes in the proportion of cells that responded. Furthermore, the duration of recruitment of the chromatin regulators determined the fraction of cells that were silenced. Thus, distinct modifiers can produce different characteristics of epigenetic memory.

Science, this issue p. 720; see also p. 661


Chromatin regulators play a major role in establishing and maintaining gene expression states. Yet how they control gene expression in single cells, quantitatively and over time, remains unclear. We used time-lapse microscopy to analyze the dynamic effects of four silencers associated with diverse modifications: DNA methylation, histone deacetylation, and histone methylation. For all regulators, silencing and reactivation occurred in all-or-none events, enabling the regulators to modulate the fraction of cells silenced rather than the amount of gene expression. These dynamics could be described by a three-state model involving stochastic transitions between active, reversibly silent, and irreversibly silent states. Through their individual transition rates, these regulators operate over different time scales and generate distinct types of epigenetic memory. Our results provide a framework for understanding and engineering mammalian chromatin regulation and epigenetic memory.

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