title: A Bayesian Change point model for differential gene expression patterns of the DosR regulon of Mycobacterium tuberculosis.
abstract: 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.
authors.affiliation: 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>
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kim A
authors.initials: KA
authors.lastname: Hatch
authors.forename: Lorenz
authors.initials: L
authors.lastname: Wernisch
authors.forename: Joanna
authors.initials: J
authors.lastname: Bacon
mesh_terms: 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
chemical_list: D001426:Bacterial Proteins; D014157:Transcription Factors; D010100:Oxygen