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

Zhang Y, Hatch KA, Wernisch L, Bacon J - BMC Genomics (2008)

Bottom Line: It results in probabilities of a change in gene expression at certain time points.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.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.

View Article: PubMed Central - HTML - PubMed

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>

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.

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.

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Upregulation of genes with high binding affinity for DosR. Figure 2 – displays the expression profiles of four early-upregulated genes and the corresponding divergently transcribed genes sharing common binding motifs. Subplot (a) shows genes with strong binding affinity for DosR up-regulated early (at the time point 2 or 3). Subplot (b) shows two pairs of divergently transcribed genes with strong binding affinity.
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Figure 2: Upregulation of genes with high binding affinity for DosR. Figure 2 – displays the expression profiles of four early-upregulated genes and the corresponding divergently transcribed genes sharing common binding motifs. Subplot (a) shows genes with strong binding affinity for DosR up-regulated early (at the time point 2 or 3). Subplot (b) shows two pairs of divergently transcribed genes with strong binding affinity.

Mentions: There are 23 TUs containing a DosR-binding site. Most of them showed marked up-regulation at time point 6 (at 0.2% DOT) and were up-regulated from time point 5 or 6. There are just four TUs deviating from this pattern in the time-course presented here.: Rv1733c, Rv1738, Rv2031c and Rv3134c, which were up-regulated from time point 2 or 3 on, earlier than the other TUs with DosR-binding sites (see Figures 2a and 2b). Closer inspection of their binding scores shows that they are among the top 6 genes with highest motif scores, suggesting that their early upregulation might be is caused by a strong promoter affinity (see Table 1).


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

Zhang Y, Hatch KA, Wernisch L, Bacon J - BMC Genomics (2008)

Upregulation of genes with high binding affinity for DosR. Figure 2 – displays the expression profiles of four early-upregulated genes and the corresponding divergently transcribed genes sharing common binding motifs. Subplot (a) shows genes with strong binding affinity for DosR up-regulated early (at the time point 2 or 3). Subplot (b) shows two pairs of divergently transcribed genes with strong binding affinity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2275270&req=5

Figure 2: Upregulation of genes with high binding affinity for DosR. Figure 2 – displays the expression profiles of four early-upregulated genes and the corresponding divergently transcribed genes sharing common binding motifs. Subplot (a) shows genes with strong binding affinity for DosR up-regulated early (at the time point 2 or 3). Subplot (b) shows two pairs of divergently transcribed genes with strong binding affinity.
Mentions: There are 23 TUs containing a DosR-binding site. Most of them showed marked up-regulation at time point 6 (at 0.2% DOT) and were up-regulated from time point 5 or 6. There are just four TUs deviating from this pattern in the time-course presented here.: Rv1733c, Rv1738, Rv2031c and Rv3134c, which were up-regulated from time point 2 or 3 on, earlier than the other TUs with DosR-binding sites (see Figures 2a and 2b). Closer inspection of their binding scores shows that they are among the top 6 genes with highest motif scores, suggesting that their early upregulation might be is caused by a strong promoter affinity (see Table 1).

Bottom Line: It results in probabilities of a change in gene expression at certain time points.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.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.

View Article: PubMed Central - HTML - PubMed

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>

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.

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.

Show MeSH
Related in: MedlinePlus