1. Computational and Systems Biology
  2. Chromosomes and Gene Expression
Download icon

Gene Expression: Bursting through the cell cycle

  1. Shani Ben-Moshe
  2. Shalev Itzkovitz  Is a corresponding author
  1. Weizmann Institute of Science, Israel
  • Cited 3
  • Views 3,897
  • Annotations
Cite this article as: eLife 2016;5:e14953 doi: 10.7554/eLife.14953


How are cells able to maintain constant levels of mRNA when the number of genes in a cell doubles ahead of cell division?

Main text

Imagine trying to maintain a constant speed while driving a car. Sounds simple enough, but what if you’re only allowed to press the accelerator pedal intermittently. As strange as this driving technique seems, cells often behave in a comparable manner when transcribing genes to produce messenger RNA (mRNA) molecules. The mRNA molecules are produced when a region of the gene called the promoter is open: since these promoters randomly switch between open and closed states, the mRNA molecules are produced in bursts. Cells also degrade mRNA, just as friction from the road reduces the speed of a car. As a result, mRNA levels will rise and fall over time (Raj and van Oudenaarden, 2008).

Now let’s go back to our car analogy and add another complication. What if a second driver miraculously appears from time to time, controlling their accelerator independently of yours? How could you possibly avoid breaking the speed limit now? With double the acceleration you would have to compensate by either reducing how often or how hard you pressed the accelerator pedal.

Cells face a similar challenge when they replicate (Figure 1). During some phases of the cell cycle, the cell contains twice as many copies of each gene as usual, which could double the amount of mRNA that is produced. How do replicating cells compensate for this so that mRNA levels remain constant? Now, in eLife, Ido Golding and colleagues – including Samuel Skinner as first author – present an elegant framework that can be used to address this question (Skinner et al., 2016).

Maintaining constant levels of mRNA throughout the cell cycle.

During the G1 phase of the cell cycle (blue), the promoter for a given gene opens and closes to produce mRNA molecules (black waves) in bursts. However, during the S phase and G2 phase of the cell cycle (green), the cell contains twice as many copies of each gene as a result of replication. Cells must therefore compensate for these extra copies in order to maintain constant mRNA levels throughout the cell cycle. Skinner et al. found that this compensation is achieved by reducing the number of times per hour that the promoter is open. The challenge of maintaining a constant level of mRNA is similar to the challenge of maintaining a constant speed in a car in which a second driver periodically appears.

Using a technique called single-molecule mRNA fluorescence in-situ hybridization, Skinner et al. – who are based at Baylor College of Medicine, Rice University, the University of Illinois at Urbana-Champaign and the Icahn School of Medicine at Mount Sinai – quantified the levels of mature and newly transcribed mRNA molecules in individual mouse embryonic stem cells. They also measured how much DNA each cell contained and used this to work out which phase of the cell cycle the cell was in. These measurements allowed the activity of each copy of a particular gene to be analyzed before and after gene replication.

Skinner et al. found that two genes that are important in embryonic stem cells, Nanog and Oct4, are transcribed in a “bursty” manner. Furthermore, this activity reduces after DNA replication to compensate for the extra DNA in the cell, thus equalizing mRNA levels over the cell cycle. A similar "dosage compensation" mechanism for altering the rate of transcription following DNA replication has been documented in other biological systems (Fraser and Nurse, 1978; Padovan-Merhar et al., 2015; Voichek et al., 2016; Yunger et al., 2010).

There are three parameters that could be reduced to achieve dosage compensation: how often a given promoter opens per hour (the burst frequency); how long it remains open for; and the rate at which mRNA is produced from an open promoter (burst size). To identify which of these parameters are relevant in mouse stem cells, Skinner et al. developed a model that accounts for the fact that the number of copies of a gene changes during the cell cycle.

A simplified model in which the burst frequency was the only parameter that changed during the cell cycle resulted in an excellent fit to the experimental data. This means that cells seem to compensate for gene replication by having each copy switch to an open state less often, rather than by reducing how many mRNAs they produce when open. Skinner et al. also found that the burst frequency was the parameter that differed most between their two studied genes, Oct4 and Nanog. These results reinforce the findings of other recent studies in mammalian cells, which identified the importance of regulating transcription rate through changes in burst frequency. This regulation can occur throughout the cell cycle (Padovan-Merhar et al., 2015), in response to transcription factor levels (Senecal et al., 2014) or in liver genes in response to metabolic stimuli (Bahar Halpern et al., 2015).

The cell cycle poses additional challenges for cells. For one, cell division immediately halves mRNA production, and so mRNA levels must increase in preparation for this event. This is achieved through a mechanism that monitors the volume of the cell and increases burst size accordingly (Padovan-Merhar et al., 2015). In addition, mRNA degradation rates vary greatly between genes, posing different constraints on burst parameters and their compensation mechanisms. Again there are parallels with driving: it is much more difficult to maintain a constant speed on a dirt track than on a major highway.

Finally, there are cases where cells amplify variability in mRNA levels to generate differences between cells. An example is the bacterial stress response, where variable mRNA levels of key genes can help to vary the response (Eldar and Elowitz, 2010). Stem cell differentiation strategies may also change depending on the stage of the cell cycle that has been reached (Pauklin and Vallier, 2013). Skinner et al. now provide the tools to identify the burst parameters that vary throughout the cell cycle for any gene and biological system of interest.


Article and author information

Author details

  1. Shani Ben-Moshe

    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Shalev Itzkovitz

    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.

Publication history

  1. Version of Record published: March 7, 2016 (version 1)


© 2016, Ben-Moshe et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 3,897
    Page views
  • 379
  • 3

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Computational and Systems Biology
    Ina Lantzsch et al.
    Research Article

    The female meiotic spindles of most animals are acentrosomal and undergo striking morphological changes while transitioning from metaphase to anaphase. The ultra-structure of acentrosomal spindles, and how changes to this structure correlate with such dramatic spindle rearrangements remains largely unknown. To address this, we applied light microscopy, large-scale electron tomography and mathematical modeling of female meiotic C. elegans spindles undergoing the transition from metaphase to anaphase. Combining these approaches, we find that meiotic spindles are dynamic arrays of short microtubules that turn over on second time scales. The results show that the transition from metaphase to anaphase correlates with an increase in the number of microtubules and a decrease in their average length. Detailed analysis of the tomographic data revealed that the length of microtubules changes significantly during the metaphase-to-anaphase transition. This effect is most pronounced for those microtubules located within 150 nm of the chromosome surface. To understand the mechanisms that drive this transition, we developed a mathematical model for the microtubule length distribution that considers microtubule growth, catastrophe, and severing. Using Bayesian inference to compare model predictions and data, we find that microtubule turn-over is the major driver of the observed large-scale reorganizations. Our data suggest that in metaphase only a minor fraction of microtubules, those that are closest to the chromosomes, are severed. The large majority of microtubules, which are not in close contact with chromosomes, do not undergo severing. Instead, their length distribution is fully explained by growth and catastrophe alone. In anaphase, even microtubules close to the chromosomes show no signs of cutting. This suggests that the most prominent drivers of spindle rearrangements from metaphase to anaphase are changes in nucleation and catastrophe rate. In addition, we provide evidence that microtubule severing is dependent on the presence of katanin.

    1. Cell Biology
    2. Computational and Systems Biology
    James Oliver Patterson et al.
    Research Article

    Maintenance of cell size homeostasis is a property that is conserved throughout eukaryotes. Cell size homeostasis is brought about by the co-ordination of cell division with cell growth, and requires restriction of smaller cells from undergoing mitosis and cell division, whilst allowing larger cells to do so. Cyclin-CDK is the fundamental driver of mitosis and therefore ultimately ensures size homeostasis. Here we dissect determinants of CDK activity in vivo to investigate how cell size information is processed by the cell cycle network in fission yeast. We develop a high-throughput single-cell assay system of CDK activity in vivo and show that inhibitory tyrosine phosphorylation of CDK encodes cell size information, with the phosphatase PP2A aiding to set a size threshold for division. CDK inhibitory phosphorylation works synergistically with PP2A to prevent mitosis in smaller cells. Finally, we find that diploid cells of equivalent size to haploid cells exhibit lower CDK activity in response to equal cyclin-CDK enzyme concentrations, suggesting that CDK activity is reduced by increased DNA levels. Therefore, scaling of cyclin-CDK levels with cell size, CDK inhibitory phosphorylation, PP2A, and DNA-dependent inhibition of CDK activity, all inform the cell cycle network of cell size, thus contributing to cell-size homeostasis.