A Bayesian Change point model for differential gene expression patterns of the DosR regulon of Mycobacterium tuberculosis.
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.


CONCLUSIONS
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.
Zhang
Yi
Y
School of Crystallography, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, UK. ezhan01@mail.cryst.bbk.ac.uk <ezhan01@mail.cryst.bbk.ac.uk>
Hatch
Kim A
KA
Wernisch
Lorenz
L
Bacon
Joanna
J
D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001499:Bayes Theorem; D001665:Binding Sites; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial / Q000235:genetics*; D008957:Models, Genetic; D005810:Multigene Family / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D018085:Regulon / Q000235:genetics*; D012984:Software; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
D001426:Bacterial Proteins; D014157:Transcription Factors; D010100:Oxygen