Transcriptional bursting, also known as transcriptional pulsing, is a fundamental property of genes in which

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, often th ...

from

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

can occur in "bursts" or "pulses", which has been observed in diverse organisms, from bacteria to mammals.

Detection of the phenomenon

This phenomenon came to light with the advent of technologies, such as MS2 tagging and single molecule RNA

fluorescence in situ hybridisation Fluorescence ''in situ'' hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes that bind to only particular parts of a nucleic acid sequence with a high degree of sequence complementarity. It was developed by ...

, 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 The northern blot, or RNA blot,Gilbert, S. F. (2000) Developmental Biology, 6th Ed. Sunderland MA, Sinauer Associates. is a technique used in molecular biology research to study gene expression by detection of RNA (or isolated mRNA) in a sample.Ke ...

microarrays A microarray is a multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of biological interactions. It is a two-dimensional array on a solid substrate—usually a glass slide or silicon thin-film cell� ...

RT-PCR Reverse transcription polymerase chain reaction (RT-PCR) is a laboratory technique combining reverse transcription of RNA into DNA (in this context called complementary DNA or cDNA) and amplification of specific DNA targets using polymerase chain ...

and

RNA-Seq RNA-Seq (named as an abbreviation of RNA sequencing) is a technique that uses next-generation sequencing to reveal the presence and quantity of RNA molecules in a biological sample, providing a snapshot of gene expression in the sample, also k ...

, 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.

Mechanism

Bursting may result from the stochastic nature of biochemical events superimposed upon a two step fluctuation. In its simplest form, the gene is proposed to 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. 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. More recent data indicate the two state model can be an oversimplification. Transcription of the c-Fos gene in response to serum stimulation can, for the most part, be summarised by two states, although at certain times after stimulation, a third state better explains the variance in the data. Another model suggests a two state model can apply, but with each cell having a different transcription rate in the active state. Other analyses indicate a spectrum or continuum of activity states. The nuclear and signaling landscapes of complex

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

nuclei may favour more than two simple states- for example, there are over several dozen post-translational modifications of nucleosomes and perhaps a hundred different proteins involved in the average eukaryotic transcription reaction. What do the repressive and permissive states represent? An attractive idea is that the repressed state is a closed

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...

conformation whilst the permissive states are more open. Another hypothesis is that the fluctuations between states reflect reversible transitions in the binding and dissociation of pre-initiation complexes. Bursts may also result from bursty signalling, cell cycle effects or movement of chromatin to and from

transcription factories Transcription factories, in genetics describe the discrete sites where Transcription (genetics), transcription occurs in the cell nucleus, and are an example of a biomolecular condensate. They were first discovered in 1993 and have been found to ...

. Bursting dynamics have been demonstrated to be influenced by cell size and the frequency of extracellular signalling. 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. Suggested mechanisms by which noise can be dampened include strong extracellular signalling, diffusion of RNA and protein in cell syncitia, promoter proximal pausing, and nuclear retention of transcripts. In certain contexts, such as the survival of microbes in rapidly changing stressful environments, the expression variability may be essential. Variability also impacts upon the effectiveness of clinical treatment, with resistance of bacteria to

antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

demonstrably caused by non-genetic differences. Similar phenomena may contribute to the resistance of sub-populations of cancer cells to chemotherapy. Spontaneous variability in gene expression is also proposed to act as a source of cell fate diversity in self-organizing differentiation processes, and may act as a barrier to effective cellular reprogramming strategies.

Notes

{{reflist Molecular genetics Gene expression Molecular biology