In silico regulatory analysis for exploring human disease progression.
BACKGROUND
An important goal in bioinformatics is to unravel the network of transcription factors (TFs) and their targets. This is important in the human genome, where many TFs are involved in disease progression. Here, classification methods are applied to identify new targets for 152 transcriptional regulators using publicly-available targets as training examples. Three types of sequence information are used: composition, conservation, and overrepresentation.


RESULTS
Starting with 8817 TF-target interactions we predict an additional 9333 targets for 152 TFs. Randomized classifiers make few predictions (approximately 2/18660) indicating that our predictions for many TFs are significantly enriched for true targets. An enrichment score is calculated and used to filter new predictions.Two case-studies for the TFs OCT4 and WT1 illustrate the usefulness of our predictions: Many predicted OCT4 targets fall into the Wnt-pathway. This is consistent with known biology as OCT4 is developmentally related and Wnt pathway plays a role in early development. Beginning with 15 known targets, 354 predictions are made for WT1. WT1 has a role in formation of Wilms' tumor. Chromosomal regions previously implicated in Wilms' tumor by cytological evidence are statistically enriched in predicted WT1 targets. These findings may shed light on Wilms' tumor progression, suggesting that the tumor progresses either by loss of WT1 or by loss of regions harbouring its targets. Targets of WT1 are statistically enriched for cancer related functions including metastasis and apoptosis. Among new targets are BAX and PDE4B, which may help mediate the established anti-apoptotic effects of WT1. Of the thirteen TFs found which co-regulate genes with WT1 (p < or = 0.02), 8 have been previously implicated in cancer. The regulatory-network for WT1 targets in genomic regions relevant to Wilms' tumor is provided.


CONCLUSIONS
We have assembled a set of features for the targets of human TFs and used them to develop classifiers for the determination of new regulatory targets. Many predicted targets are consistent with the known biology of their regulators, and new targets for the Wilms' tumor regulator, WT1, are proposed. We speculate that Wilms' tumor development is mediated by chromosomal rearrangements in the location of WT1 targets.
Holloway
Dustin T
DT
Molecular Biology Cell Biology and Biochemistry Department, Boston University, 5 Cummington Street, Boston, USA.
Kon
Mark
M
DeLisi
Charles
C
D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D018390:Gene Targeting; D016162:Genes, Wilms Tumor / Q000502:physiology; D006801:Humans; D008957:Models, Genetic; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011237:Predictive Value of Tests; D011485:Protein Binding / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000145:classification / Q000378:metabolism / Q000502:physiology*; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D014157:Transcription Factors; D025721:WT1 Proteins