Decision letter | A long-term epigenetic memory switch controls bacterial virulence bimodality

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A long-term epigenetic memory switch controls bacterial virulence bimodality

Decision letter

Affiliation details

The Hebrew University of Jerusalem, Israel
Michael Laub, Reviewing editor, Massachusetts Institute of Technology, United States

In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.

Thank you for submitting your article "A Long-term Epigenetic Memory Switch Controls Bacterial Virulence Bimodality" for consideration by eLife. Your article has been reviewed by two peer reviewers, including Jose Luis Puente (Reviewer #3), and the evaluation has been overseen by a Reviewing Editor and Richard Losick as the Senior Editor.

The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.


The reviewers agreed that this is a very nice paper that describes phenotypic variability in the EPEC strain E2348/69, demonstrating that the variability is likely associated with the plasmid-encoded PerA transcriptional regulator. The variable phenotype involves both growth rate as well as virulence gene expression. A particularly striking feature of the variability described here is the remarkable stability of the small morphotype subpopulation under non-activating conditions. The authors present a thorough analysis of the phenomenon and have taken the first steps towards establishing a mechanism through their identification of PerA as playing a central role. Although there was enthusiasm among the reviewers and reviewing editor, there were also some concerns. First, the paper makes little headway in establishing how PerA bimodality is achieved in a population. Understanding the origins of bimodality would elevate the paper's impact substantially, although it was agreed that a full understanding of this would be beyond the scope of a single paper. Second, and perhaps more importantly, there were concerns about whether the data unequivocally support the conclusion that PerA is the sole arbiter of the phenotypic variability. This issue, in particular, will need to be fully addressed in a revised manuscript – please see the revisions below for details.

Essential revisions:

The authors have not fully ruled out that PerB may also play a role in controlling bimodality as the perA deletion (and insertion of a kanR cassette) may have a polar effect on perB. Additionally, the perA mutant was complemented by putting back a plasmid with the entire perABC operon, and a perB deletion mutant was not tested. Also, the bimodal expression of the perABC operon is in agreement with colony-size bimodality, but the experiments performed don't rule out the possibility that something else on the plasmid or the chromosome contributes to phenotypic variability. Thus, a revised manuscript should:

1) Perform a complementation experiment as shown in the bottom middle panel of Figure 4B but using a plasmid that expresses only perA, instead of perABC. This will establish that the loss of bimodality in the perA deletion is due to the lack of PerA and not due to a change in PerB expression.

2) Also, perform a complementation experiment, as in Figure 4B, in which the plasmid expressing perA alone is put into a strain that lacks the EAF plasmid, to determine whether PerA alone or through other PerA-regulated component of the EAF plasmid, is required for bimodality.

3) If PerA alone fails to fully complement in 1) then the two complementation experiments above should be done with PerB alone.