BACKGROUND: Low oxygen availability has been shown previously to stimulate M. 
tuberculosis to establish non-replicative persistence in vitro. The two 
component sensor/regulator dosRS is a major mediator in the transcriptional 
response of M. tuberculosis to hypoxia and controls a regulon of approximately 
50 genes that are induced under this condition. The aim of this study was to 
determine whether the induction of the entire DosR regulon is triggered as a 
synchronous event or if induction can unfold as a cascade of events as the 
differential expression of subsets of genes is stimulated by different oxygen 
availabilities.
RESULTS: A novel aspect of our work is the use of chemostat cultures of M. 
tuberculosis which allowed us to control environmental conditions very tightly. 
We exposed M. tuberculosis to a sudden drop in oxygen availability in chemostat 
culture and studied the transcriptional response of the organism during the 
transition from a high oxygen level (10% dissolved oxygen tension or DOT) to a 
low oxygen level (0.2% DOT) using DNA microarrays. We developed a Bayesian 
change point analysis method that enabled us to detect subtle shifts in the 
timing of gene induction. It results in probabilities of a change in gene 
expression at certain time points. A computational analysis of potential binding 
sites upstream of the DosR-controlled genes shows how the transcriptional 
responses of these genes are influenced by the affinity of these binding sites 
to DosR. Our study also indicates that a subgroup of DosR-controlled genes is 
regulated indirectly.
CONCLUSION: The majority of the dosR-dependent genes were up-regulated at 0.2% 
DOT, which confirms previous findings that these genes are triggered by hypoxic 
environments. However, our change point analysis also highlights genes which 
were up-regulated earlier at levels of about 8% DOT indicating that they respond 
to small fluctuations in oxygen availability. Our analysis shows that there are 
pairs of divergent genes where one gene in the pair is up-regulated before the 
other, presumably for a flexible response to a constantly changing environment 
in the host.