Transcriptional bursting

Transcriptional bursting, also known as transcriptional pulsing, is a fundamental property of genes from bacteria to humans. Transcription of genes, the process which transforms the stable code written in DNA into the mobile RNA message can occur in "bursts" or "pulses". This phenomenon has recently come to light with the advent of new technologies, such as MS2 tagging, to detect RNA production in single cells, allowing 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 transcription is a continuous smooth process. The reality is that transcription is irregular, with strong periods of activity, interspersed by long periods of inactivity. Averaged over millions of cells, this appears continuous. But at the individual cell level, there is considerable variability, and for most genes, very little activity at any one time.

Bursting may result from the stochastic nature of biochemical events superimposed upon a 2 or more step fluctuation. In its most simple form, the gene can exist in 2 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 are likely to 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.

The bursting phenomenon, as opposed to simple probabilistic models of transcription, can account for the high variability (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.