Referee 1's review:

Rustad and colleagues have shown through microarray experiments, targeted deletion studies and murine challenge data that the DosR regulon is perhaps not as important as previously thought, and that MTB has a more prolonged (enduring) hypoxic response. The manuscript is well written, it flows logically and the claims are well substantiated.

The authors should try to paginate submissions to make it easier to provide page-directed feedback.

Under "transcriptional analysis of a hypoxic time course", the authors state that the ~50 genes of the DosR regulon are maximally induced early. A brief look at Table S1 indicates that several genes appeared suppressed, for instance Rv3128c gave ratios around 0.02. Is the DosR regulon uni-directional (only induction) or does it also comprise genes that are shut down? Also, in the table a few genes had a negative sign, should the authors consider setting genes where background exceeds signal to '1', to resolve this analytic problem when there is effectively signal in one experimental channel and nothing with the other channel?

Discussion: "In vitro, MTB lacking DosR show no ..." I found this sentence hard to digest, because of the 'and' followed later by a 'but also'. Could the authors break this into a couple of shorter, crisper sentences?

The paragraph beginning: "Rarely....". I followed the logic until (44-47), but then the authors switched from induction of DosR to repression of DosR. For a reader not familiar with this field of research, this could be confusing. Is the default setting that the regulon is OFF, unless specifically induced (by e.g. hypoxia)? Or is it felt that the regulon is typically ON, unless repressed? I think the authors should try to flesh this out with one-two extra sentences in this paragraph, so that the reader has a clearer understanding of when DosR is ON, when DosR is OFF, and when DosR matters.

In the methods section, I did not see in the in vivo material how gene expression in vivo was determined (Rv0081, Rv2031c). Was this placed elsewhere?

Supporting table S2 was cut-off in the pdf translation. I only got down to Rv0031, I don't know how much further this went. Be careful that the whole table gets copied in the final manuscript.

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.