Gene expression · Single-cell
Genes fire in bursts, and the randomness is built into the gene
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Short answer
Mammalian transcription proceeds in infrequent random bursts, and the resulting cell-to-cell variation is intrinsic to the locus rather than inherited from differences between cells.
What happened
Raj and colleagues used fluorescence in situ hybridisation to count single reporter and native mRNA molecules in clonal mammalian cells, then tested whether the spread across cells came from intrinsic randomness or from extrinsic differences between cells. Genes transitioned between active and inactive states infrequently, producing bursts. The variability was predominantly intrinsic, and it affected whole genomic loci, including the RNA polymerase II large-subunit transcript.
Why it matters
A population measurement reports an average expression level, which implies a rate. Single-molecule counting shows that no individual cell is transcribing at that rate — they are switching between off and bursting. Any model fitted to the average is fitting a quantity that describes none of the cells.
Evidence
- Study type
- Single-molecule FISH counting in clonal mammalian cells with an intrinsic/extrinsic noise decomposition
- Sample
- Individual mRNA counts across clonal cell populations; reporter and endogenous loci
- Journal
- PLoS Biology · peer reviewed
- Replication
- Bursting has since been confirmed across organisms and is now the standard description of transcription
- Limitations
- Clonal cells in culture, not tissue. The decomposition shows the variation is intrinsic without identifying the molecular switch responsible, and burst kinetics are not mapped genome-wide.
What this connects to
Sources
The 2 studies this explanation is built from, by the role each plays. Every source links to PaperFren’s explanation of it and to the original paper.
Supporting evidence
- Genetics shapes methylation and expression
In HapMap LCLs, promoter methylation associates with genetic variants and transcript levels.
What it does not showLimitations
LCLs are transformed lines, so results may differ from primary tissues.
PaperFren explanationStudy with cards and a quizOriginal paper (DOI)cc by
Landmark research
- Why do identical cells make different amounts of mRNA?
Mammalian genes switch rarely between ON and OFF, so intrinsically random transcriptional bursts create large cell-to-cell mRNA differences.
What it does not showLimitations
Does not map every mammalian gene’s burst kinetics in vivo tissues, or prove a single molecular switch mechanism for all loci.
PaperFren explanationStudy with cards and a quizOriginal paper (DOI)cc by
Before
Expression levels were measured across populations and modelled as continuous rates, with cell-to-cell variation attributed largely to differences in cell state, size or cycle position.
Now
Bursting is a property of the gene, and the intrinsic/extrinsic decomposition attributes most of the spread to the locus. The study does not map burst kinetics for every gene or in tissue, and it does not identify a single molecular switch.