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Genome-scale study of the importance of binding site context for transcription factor binding and gene regulation.

Westholm JO, Xu F, Ronne H, Komorowski J - BMC Bioinformatics (2008)

Bottom Line: We used ContextFinder to examine the role of motif context in S. cerevisiae both for DNA binding by transcription factors and for effects on gene expression.We validated our results against data on nucleosome positioning, and found a negative correlation between preferred motif locations and nucleosome occupancy.We conclude that the requirement for stable binding of transcription factors to DNA and their subsequent function in gene regulation can impose constraints on motif context.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Linnaeus Centre for Bioinformatics, Uppsala University, Uppsala, Sweden. jakub@lcb.uu.se

ABSTRACT

Background: The rate of mRNA transcription is controlled by transcription factors that bind to specific DNA motifs in promoter regions upstream of protein coding genes. Recent results indicate that not only the presence of a motif but also motif context (for example the orientation of a motif or its location relative to the coding sequence) is important for gene regulation.

Results: In this study we present ContextFinder, a tool that is specifically aimed at identifying cases where motif context is likely to affect gene regulation. We used ContextFinder to examine the role of motif context in S. cerevisiae both for DNA binding by transcription factors and for effects on gene expression. For DNA binding we found significant patterns of motif location bias, whereas motif orientations did not seem to matter. Motif context appears to affect gene expression even more than it affects DNA binding, as biases in both motif location and orientation were more frequent in promoters of co-expressed genes. We validated our results against data on nucleosome positioning, and found a negative correlation between preferred motif locations and nucleosome occupancy.

Conclusion: We conclude that the requirement for stable binding of transcription factors to DNA and their subsequent function in gene regulation can impose constraints on motif context.

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Anti-correlation between motif frequency and nucleosome occupancy. A) An example of anti-correlation between motif frequency and nucleosome occupancy. The black curve shows the distribution of Ste12 binding motifs within promoters bound by Ste12. The red curve shows the average nucleosome occupancy levels around these Ste12 sites. The correlation in this example is -0.79. B) Histogram over the correlation between motif frequency and nucleosome occupancy for all 280 motif-experiment pairs from the TF-DNA interaction data. Pairs with a significant location bias (in red) have significantly lower correlations (p-value 2.9e-3) than pairs without correlation bias (blue).
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Figure 5: Anti-correlation between motif frequency and nucleosome occupancy. A) An example of anti-correlation between motif frequency and nucleosome occupancy. The black curve shows the distribution of Ste12 binding motifs within promoters bound by Ste12. The red curve shows the average nucleosome occupancy levels around these Ste12 sites. The correlation in this example is -0.79. B) Histogram over the correlation between motif frequency and nucleosome occupancy for all 280 motif-experiment pairs from the TF-DNA interaction data. Pairs with a significant location bias (in red) have significantly lower correlations (p-value 2.9e-3) than pairs without correlation bias (blue).

Mentions: Since nucleosomes and TFs frequently compete for binding to DNA, nucleosome positions affect the DNA binding of many TFs. Furthermore, it has been shown that active TF binding sites are depleted of nucleosomes, as compared to inactive sites [27,28]. We therefore proceeded to use available nucleosome position data from yeast in an attempt to validate our results. Specifically, we expected motifs in preferred locations to be more likely to be biologically active than motifs in other locations, and thus also to be more likely to be depleted of nucleosomes than motifs in other locations. As expected, we found that nucleosome occupancy shows an inverse correlation with motif occurrence in promoters that bind a given TF. This is illustrated in Figure 5A for promoters that bind Ste12. When the entire set of data from the TF-DNA interaction studies [19,32] was examined, we found that instances with location bias for DNA binding show significantly (p-value 2.9e-3) higher anti-correlation between nucleosome occupancy and motif occurrence than instances without location bias (Fig 5b, for full results see additional file 3: Table S3). We conclude that motifs in preferred locations generally have less nucleosomes bound at or near them than motifs in other locations. In contrast, we did not see the same effect for motifs in promoters of co-expressed genes (p-value 0.16). We note, however, that much of the protein-DNA interaction data was obtained during exponential growth on YPD (Yeast Peptone Dextrose) as was the nucleosome occupancy data, while the expression data was obtained during several different conditions. Furthermore, there were fewer motif-group pairs in this case than for the DNA binding data, which makes this negative result harder to interpret.


Genome-scale study of the importance of binding site context for transcription factor binding and gene regulation.

Westholm JO, Xu F, Ronne H, Komorowski J - BMC Bioinformatics (2008)

Anti-correlation between motif frequency and nucleosome occupancy. A) An example of anti-correlation between motif frequency and nucleosome occupancy. The black curve shows the distribution of Ste12 binding motifs within promoters bound by Ste12. The red curve shows the average nucleosome occupancy levels around these Ste12 sites. The correlation in this example is -0.79. B) Histogram over the correlation between motif frequency and nucleosome occupancy for all 280 motif-experiment pairs from the TF-DNA interaction data. Pairs with a significant location bias (in red) have significantly lower correlations (p-value 2.9e-3) than pairs without correlation bias (blue).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2629780&req=5

Figure 5: Anti-correlation between motif frequency and nucleosome occupancy. A) An example of anti-correlation between motif frequency and nucleosome occupancy. The black curve shows the distribution of Ste12 binding motifs within promoters bound by Ste12. The red curve shows the average nucleosome occupancy levels around these Ste12 sites. The correlation in this example is -0.79. B) Histogram over the correlation between motif frequency and nucleosome occupancy for all 280 motif-experiment pairs from the TF-DNA interaction data. Pairs with a significant location bias (in red) have significantly lower correlations (p-value 2.9e-3) than pairs without correlation bias (blue).
Mentions: Since nucleosomes and TFs frequently compete for binding to DNA, nucleosome positions affect the DNA binding of many TFs. Furthermore, it has been shown that active TF binding sites are depleted of nucleosomes, as compared to inactive sites [27,28]. We therefore proceeded to use available nucleosome position data from yeast in an attempt to validate our results. Specifically, we expected motifs in preferred locations to be more likely to be biologically active than motifs in other locations, and thus also to be more likely to be depleted of nucleosomes than motifs in other locations. As expected, we found that nucleosome occupancy shows an inverse correlation with motif occurrence in promoters that bind a given TF. This is illustrated in Figure 5A for promoters that bind Ste12. When the entire set of data from the TF-DNA interaction studies [19,32] was examined, we found that instances with location bias for DNA binding show significantly (p-value 2.9e-3) higher anti-correlation between nucleosome occupancy and motif occurrence than instances without location bias (Fig 5b, for full results see additional file 3: Table S3). We conclude that motifs in preferred locations generally have less nucleosomes bound at or near them than motifs in other locations. In contrast, we did not see the same effect for motifs in promoters of co-expressed genes (p-value 0.16). We note, however, that much of the protein-DNA interaction data was obtained during exponential growth on YPD (Yeast Peptone Dextrose) as was the nucleosome occupancy data, while the expression data was obtained during several different conditions. Furthermore, there were fewer motif-group pairs in this case than for the DNA binding data, which makes this negative result harder to interpret.

Bottom Line: We used ContextFinder to examine the role of motif context in S. cerevisiae both for DNA binding by transcription factors and for effects on gene expression.We validated our results against data on nucleosome positioning, and found a negative correlation between preferred motif locations and nucleosome occupancy.We conclude that the requirement for stable binding of transcription factors to DNA and their subsequent function in gene regulation can impose constraints on motif context.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Linnaeus Centre for Bioinformatics, Uppsala University, Uppsala, Sweden. jakub@lcb.uu.se

ABSTRACT

Background: The rate of mRNA transcription is controlled by transcription factors that bind to specific DNA motifs in promoter regions upstream of protein coding genes. Recent results indicate that not only the presence of a motif but also motif context (for example the orientation of a motif or its location relative to the coding sequence) is important for gene regulation.

Results: In this study we present ContextFinder, a tool that is specifically aimed at identifying cases where motif context is likely to affect gene regulation. We used ContextFinder to examine the role of motif context in S. cerevisiae both for DNA binding by transcription factors and for effects on gene expression. For DNA binding we found significant patterns of motif location bias, whereas motif orientations did not seem to matter. Motif context appears to affect gene expression even more than it affects DNA binding, as biases in both motif location and orientation were more frequent in promoters of co-expressed genes. We validated our results against data on nucleosome positioning, and found a negative correlation between preferred motif locations and nucleosome occupancy.

Conclusion: We conclude that the requirement for stable binding of transcription factors to DNA and their subsequent function in gene regulation can impose constraints on motif context.

Show MeSH