Transcriptional bursting

Transcriptional bursting, also known as transcriptional pulsing, is a fundamental property of genes in which transcription from DNA to RNA can occur in "bursts" or "pulses", which has been observed in diverse organisms, from bacteria to mammals. This phenomenon came to light with the advent of technologies, such as MS2 tagging and single molecule RNA fluorescence in situ hybridisation, to detect RNA production in single cells, through precise measurements of RNA number or RNA appearance at the gene. Other, more widespread techniques, such as Northern blotting, microarrays, RT-PCR and RNA-Seq, measure bulk RNA levels from homogenous population extracts. These techniques lose dynamic information from individual cells and give the impression that transcription is a continuous smooth process. Observed at an individual cell level, transcription is irregular, with strong periods of activity interspersed by long periods of inactivity.

Bursting may result from the stochastic nature of biochemical events superimposed upon a two step fluctuation. In its most simple form, the gene can exist in two states, one where activity is negligible and one where there is a certain probability of activation. Only in the second state does transcription readily occur. Whilst the nuclear and signaling landscapes of complex eukaryotic nuclei may favour more than two simple states- for example, there are over twenty post-translational modifications of nucleosomes known, this simple two step model perhaps provides a reasonable intellectual framework for understanding the changing probabilities affecting transcription. It seems likely that some rudimentary eukaryotes have genes which do not show bursting. The genes are always in the permissive state, with a simple probability describing the numbers of RNAs generated.

What do the repressive and permissive states represent? An attractive idea is that the repressed state is a closed chromatin conformation whilst the permissive state is an open one. Another hypothesis is that the fluctuations reflect transition between bound pre-initiation complexes (permissive) and dissociated ones (restrictive). Bursts may also result from bursty signalling, cell cycle effects or movement of chromatin to and from transcription factories. Recent data suggest different degrees of supercoiling distinguish the permissive and inactive states.

The bursting phenomenon, as opposed to simple probabilistic models of transcription, can account for the high variability (see transcriptional noise) in gene expression occurring between cells in isogenic populations. This variability in turn can have tremendous consequences on cell behaviour, and must be mitigated or integrated. In certain contexts, such as the survival of microbes in rapidly changing stressful environments, or several types of scattered differentiation, the variability may be essential. Variability also impacts upon the effectiveness of clinical treatment, with resistance of bacteria to antibiotics demonstrably caused by non-genetic differences. Variability in gene expression may also contribute to resistance of sub-populations of cancer cells to chemotherapy.