Transcriptional Infidelity Promotes Heritable Phenotypic Change in a Bistable Gene Network.
Gordon AJE, Halliday JA, Blankschien MD, Burns PA, Yatagai F, et al. (2009)
PLoS Biol 7(2): e1000044 doi:10.1371/journal.pbio.1000044
Bistable epigenetic switches are fundamental for cell fate determination in unicellular and multicellular organisms. Regulatory proteins associated with bistable switches are often present in low numbers and subject to molecular noise. It is becoming clear that noise in gene expression can influence cell fate. Although the origins and consequences of noise have been studied, the stochastic and transient nature of RNA errors during transcription has not been considered in the origin or modeling of noise nor has the capacity for such transient errors in information transfer to generate heritable phenotypic change been discussed. We used a classic bistable memory module to monitor and capture transient RNA errors: the lac operon of Escherichia coli comprises an autocatalytic positive feedback loop producing a heritable all-or-none epigenetic switch that is sensitive to molecular noise. Using single-cell analysis, we show that the frequency of epigenetic switching from one expression state to the other is increased when the fidelity of RNA transcription is decreased due to error-prone RNA polymerases or to the absence of auxiliary RNA fidelity factors GreA and GreB (functional analogues of eukaryotic TFIIS). Therefore, transcription infidelity contributes to molecular noise and can effect heritable phenotypic change in genetically identical cells in the same environment. Whereas DNA errors allow genetic space to be explored, RNA errors may allow epigenetic or expression space to be sampled. Thus, RNA infidelity should also be considered in the heritable origin of altered or aberrant cell behaviour.
Author Summary
Errors in information transfer from DNA to RNA to protein are
inevitable and ubiquitous. When errors that occur in DNA are not
repaired and become fixed as permanent mutations, they can have
heritable phenotypic consequences for cells. In contrast, errors that
occur during RNA transcription are considered transient, because
the life span of mRNAs and their encoded proteins is thought to be
too short to have heritable consequences. Here, we show that
transient errors that arise during transcription can cause a heritable
phenotypic change within a population of genetically identical
Escherichia coli cells growing in the same environment. We used
single-cell observation of the bistable lac operon (which allows a cell
to have two alternate states) in a stable ON or OFF state. We show
that the epigenetic-switch frequency from the OFF to ON state is
increased when the fidelity of RNA transcription is altered: bacterial
strains that contain error-prone RNA polymerases, ‘‘RNA mutators,’’
and strains deficient in auxiliary RNA fidelity factors exhibit an
increased epigenetic-switch frequency compared with wild-type
strains. Therefore, like DNA mutation, transient stochastic events can
also have long-lived heritable consequences for the cell.
