A continuum model of transcriptional bursting

Understanding how gene activity is regulated relies on accurate measurements of the output of genes. Proteins are generated from genes via a multi-step process. In the first step, called transcription, the DNA of a gene is copied by complex cell machinery to create molecules of mRNA. Subsequently, these mRNA molecules are ‘translated’ into proteins. Previous studies have assayed gene transcription by measuring mRNA production in millions of cells at the same time. The resulting measurements give the impression that transcription occurs as a continuous, smooth process. However, when individual gene transcription is measured in single cells, mRNA production between cells is unexpectedly variable. This challenged the view that transcription is a continuous process. One idea that explains this variability – the "two-state" or "bursting" model – proposes that genes switch between "on" and "off" states with a certain probability. Thus, at any one time, a gene will be off in many cells and on in others. However, the methods used in these experiments measure mRNA in dead cells, and so the dynamic switching of genes between on and off states was presumed, but not accurately measured. Corrigan et al. have now imaged the transcription of a single gene – a gene for a protein called actin – in living cells of an amoeba called Dictyostelium. Genetic techniques and computational modeling were then used to explore what affects the variability in this gene’s activity. These approaches revealed that transcription occurs across a spectrum of activity, rather than in rigid on or off states. The transcription process itself may also contribute to where a gene’s activity sits on this spectrum. Furthermore, Corrigan et al. found that a specific DNA sequence found at the start of the actin gene, that is also found in many genes in complex life-forms, is required for the gene to reach the highest levels of activity on the spectrum. This spectrum of activity states could allow cells to finely tune their responses to the signals they receive. A future challenge will be to assess how the activity of other genes compare to the actin gene and to discover what underlies the variation in the timing of transcription’s different stages.