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Identification of direct target genes using joint sequence and expression likelihood with application to DAF-16.

Yu RX, Liu J, True N, Wang W - PLoS ONE (2008)

Bottom Line: TRANSMODIS removed elements of arbitrariness in manual target gene selection process and produced results that concur with one's intuition.We found that 189 genes were tightly regulated by DAF-16.In addition, DAF-16 has differential preference for motifs when acting as an activator or repressor, which awaits experimental verification.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
A major challenge in the post-genome era is to reconstruct regulatory networks from the biological knowledge accumulated up to date. The development of tools for identifying direct target genes of transcription factors (TFs) is critical to this endeavor. Given a set of microarray experiments, a probabilistic model called TRANSMODIS has been developed which can infer the direct targets of a TF by integrating sequence motif, gene expression and ChIP-chip data. The performance of TRANSMODIS was first validated on a set of transcription factor perturbation experiments (TFPEs) involving Pho4p, a well studied TF in Saccharomyces cerevisiae. TRANSMODIS removed elements of arbitrariness in manual target gene selection process and produced results that concur with one's intuition. TRANSMODIS was further validated on a genome-wide scale by comparing it with two other methods in Saccharomyces cerevisiae. The usefulness of TRANSMODIS was then demonstrated by applying it to the identification of direct targets of DAF-16, a critical TF regulating ageing in Caenorhabditis elegans. We found that 189 genes were tightly regulated by DAF-16. In addition, DAF-16 has differential preference for motifs when acting as an activator or repressor, which awaits experimental verification. TRANSMODIS is computationally efficient and robust, making it a useful probabilistic framework for finding immediate targets.

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Comparison between the expression profiles of PHO81 and its two homologs SPL2 and YPL110C in the eight TFPE experiments of Pho4p.Red and green colors represent up- and down-regulation, respectively. The brightness of the color is proportional to the absolute expression ratio.
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pone-0001821-g001: Comparison between the expression profiles of PHO81 and its two homologs SPL2 and YPL110C in the eight TFPE experiments of Pho4p.Red and green colors represent up- and down-regulation, respectively. The brightness of the color is proportional to the absolute expression ratio.

Mentions: There were nine genes reported to be PHO-regulated prior to the study of Ogawa et al. These nine genes were PHO11, PHO5, PHO89, PHO8, SPL2, PHO12, PHO86, PHO84 and PHO81[23]–[28]. All of them except PHO81 were correctly identified as targets by both Ogawa et al. and TRANSMODIS. A heatmap of the expression profiles of PHO81 and its two homologs YPL110C and SPL2 is shown in Figure 1. The heatmap reveals that SPL2 had a consistently higher differential expression in all experiments (an average increase of 16-fold) than PHO81 and YPL110C (an average increase of 1.6-fold and 2-fold respectively) (p-value = 0.015 from two-sample t-test) (Figure 1). Indeed, both Ogawa et al. and TRANSMODIS identified SPL2 as a Pho4p target. Based on the gene expression data, the selection of SPL2 and the omission of PHO81 and YPL110C by TRANSMODIS are consistent with one's intuition.


Identification of direct target genes using joint sequence and expression likelihood with application to DAF-16.

Yu RX, Liu J, True N, Wang W - PLoS ONE (2008)

Comparison between the expression profiles of PHO81 and its two homologs SPL2 and YPL110C in the eight TFPE experiments of Pho4p.Red and green colors represent up- and down-regulation, respectively. The brightness of the color is proportional to the absolute expression ratio.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2266795&req=5

pone-0001821-g001: Comparison between the expression profiles of PHO81 and its two homologs SPL2 and YPL110C in the eight TFPE experiments of Pho4p.Red and green colors represent up- and down-regulation, respectively. The brightness of the color is proportional to the absolute expression ratio.
Mentions: There were nine genes reported to be PHO-regulated prior to the study of Ogawa et al. These nine genes were PHO11, PHO5, PHO89, PHO8, SPL2, PHO12, PHO86, PHO84 and PHO81[23]–[28]. All of them except PHO81 were correctly identified as targets by both Ogawa et al. and TRANSMODIS. A heatmap of the expression profiles of PHO81 and its two homologs YPL110C and SPL2 is shown in Figure 1. The heatmap reveals that SPL2 had a consistently higher differential expression in all experiments (an average increase of 16-fold) than PHO81 and YPL110C (an average increase of 1.6-fold and 2-fold respectively) (p-value = 0.015 from two-sample t-test) (Figure 1). Indeed, both Ogawa et al. and TRANSMODIS identified SPL2 as a Pho4p target. Based on the gene expression data, the selection of SPL2 and the omission of PHO81 and YPL110C by TRANSMODIS are consistent with one's intuition.

Bottom Line: TRANSMODIS removed elements of arbitrariness in manual target gene selection process and produced results that concur with one's intuition.We found that 189 genes were tightly regulated by DAF-16.In addition, DAF-16 has differential preference for motifs when acting as an activator or repressor, which awaits experimental verification.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
A major challenge in the post-genome era is to reconstruct regulatory networks from the biological knowledge accumulated up to date. The development of tools for identifying direct target genes of transcription factors (TFs) is critical to this endeavor. Given a set of microarray experiments, a probabilistic model called TRANSMODIS has been developed which can infer the direct targets of a TF by integrating sequence motif, gene expression and ChIP-chip data. The performance of TRANSMODIS was first validated on a set of transcription factor perturbation experiments (TFPEs) involving Pho4p, a well studied TF in Saccharomyces cerevisiae. TRANSMODIS removed elements of arbitrariness in manual target gene selection process and produced results that concur with one's intuition. TRANSMODIS was further validated on a genome-wide scale by comparing it with two other methods in Saccharomyces cerevisiae. The usefulness of TRANSMODIS was then demonstrated by applying it to the identification of direct targets of DAF-16, a critical TF regulating ageing in Caenorhabditis elegans. We found that 189 genes were tightly regulated by DAF-16. In addition, DAF-16 has differential preference for motifs when acting as an activator or repressor, which awaits experimental verification. TRANSMODIS is computationally efficient and robust, making it a useful probabilistic framework for finding immediate targets.

Show MeSH
Related in: MedlinePlus