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Latent Semantic Indexing of PubMed abstracts for identification of transcription factor candidates from microarray derived gene sets.

ABSTRACT: Identification of transcription factors (TFs) responsible for modulation of differentially expressed genes is a key step in deducing gene regulatory pathways. Most current methods identify TFs by searching for presence of DNA binding motifs in the promoter regions of co-regulated genes. However, this strategy may not always be useful as presence of a motif does not necessarily imply a regulatory role. Conversely, motif presence may not be required for a TF to regulate a set of genes. Therefore, it is imperative to include functional (biochemical and molecular) associations, such as those found in the biomedical literature, into algorithms for identification of putative regulatory TFs that might be explicitly or implicitly linked to the genes under investigation.In this study, we present a Latent Semantic Indexing (LSI) based text mining approach for identification and ranking of putative regulatory TFs from microarray derived differentially expressed genes (DEGs). Two LSI models were built using different term weighting schemes to devise pair-wise similarities between 21,027 mouse genes annotated in the Entrez Gene repository. Amongst these genes, 433 were designated TFs in the TRANSFAC database. The LSI derived TF-to-gene similarities were used to calculate TF literature enrichment p-values and rank the TFs for a given set of genes. We evaluated our approach using five different publicly available microarray datasets focusing on TFs Rel, Stat6, Ddit3, Stat5 and Nfic. In addition, for each of the datasets, we constructed gold standard TFs known to be functionally relevant to the study in question. Receiver Operating Characteristics (ROC) curves showed that the log-entropy LSI model outperformed the tf-normal LSI model and a benchmark co-occurrence based method for four out of five datasets, as well as motif searching approaches, in identifying putative TFs.Our results suggest that our LSI based text mining approach can complement existing approaches used in systems biology research to decipher gene regulatory networks by providing putative lists of ranked TFs that might be explicitly or implicitly associated with sets of DEGs derived from microarray experiments. In addition, unlike motif searching approaches, LSI based approaches can reveal TFs that may indirectly regulate genes.

SUBMITTER: Roy S

PROVIDER: S-EPMC3236841 | biostudies-other | 2011 Oct

REPOSITORIES: biostudies-other

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Latent Semantic Indexing of PubMed abstracts for identification of transcription factor candidates from microarray derived gene sets.

Roy Sujoy S Heinrich Kevin K Phan Vinhthuy V Berry Michael W MW Homayouni Ramin R

BMC bioinformatics 20111018

<h4>Background</h4>Identification of transcription factors (TFs) responsible for modulation of differentially expressed genes is a key step in deducing gene regulatory pathways. Most current methods identify TFs by searching for presence of DNA binding motifs in the promoter regions of co-regulated genes. However, this strategy may not always be useful as presence of a motif does not necessarily imply a regulatory role. Conversely, motif presence may not be required for a TF to regulate a set of ...[more]

PMID: 22165960

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Project description:BackgroundIdentification of subcellular localization in proteins is crucial to elucidate cellular processes and molecular functions in a cell. However, given a tremendous amount of sequence data generated in the post-genomic era, determining protein localization based on biological experiments can be expensive and time-consuming. Therefore, developing prediction systems to analyze uncharacterised proteins efficiently has played an important role in high-throughput protein analyses. In a eukaryotic cell, many essential biological processes take place in the nucleus. Nuclear proteins shuttle between nucleus and cytoplasm based on recognition of nuclear translocation signals, including nuclear localization signals (NLSs) and nuclear export signals (NESs). Currently, only a few approaches have been developed specifically to predict nuclear localization using sequence features, such as putative NLSs. However, it has been shown that prediction coverage based on the NLSs is very low. In addition, most existing approaches only attained prediction accuracy and Matthew's correlation coefficient (MCC) around 54%~70% and 0.250~0.380 on independent test set, respectively. Moreover, no predictor can generate sequence motifs to characterize features of potential NESs, in which biological properties are not well understood from existing experimental studies.ResultsIn this study, first we propose PSLNuc (Protein Subcellular Localization prediction for Nucleus) for predicting nuclear localization in proteins. First, for feature representation, a protein is represented by gapped-dipeptides and the feature values are weighted by homology information from a smoothed position-specific scoring matrix. After that, we incorporate probabilistic latent semantic indexing (PLSI) for feature reduction. Finally, the reduced features are used as input for a support vector machine (SVM) classifier. In addition to PSLNuc, we further identify gapped-dipeptide signatures for putative NLSs and NESs to develop a prediction method, PSLNTS (Protein Subcellular Localization prediction using Nuclear Translocation Signals). We apply PLSI to generate gapped-dipeptide signatures from both nuclear and non-nuclear proteins, and propose candidate sequence motifs for putative NLSs and NESs. Then, we incorporate only the proposed gapped-dipeptide signatures in an SVM classifier to mimic biological properties of NLSs and NESs for predicting nuclear localization in PSLNTS.ConclusionsExperiment results demonstrate that the proposed method shows a significant improvement for nuclear localization prediction. To compare our predictive performance with other approaches, we incorporate two non-redundant benchmark data sets, a training set and an independent test set. Evaluated by five-fold cross-validation on the training set, PSLNuc attains an overall accuracy of 79.7%, which is 4.8% improvement over the state-of-the-art system. In addition, our method also enhances the MCC from 0.497 to 0.595. Compared on the independent test set, PSLNuc outperforms other predictors by 3.9%~19.9% on accuracy and 0.077~0.207 on MCC. This suggests that, in addition to NLSs, which have been shown important for nuclear proteins, NESs can also be an effective indicator to detect non-nuclear proteins. Most notably, using only a few proposed gapped-dipeptide signatures as input features for the SVM classifier, PSLNTS further enhances the accuracy and MCC to 80.9% and 0.618, respectively. Our results demonstrate that gapped-dipeptide signatures can better discriminate nuclear and non-nuclear proteins. Moreover, the proposed gapped-dipeptide signatures can be biologically interpreted and used in further experiment analyses of nuclear translocation signals, including NLSs and NESs.

Dataset Information

Latent Semantic Indexing of PubMed abstracts for identification of transcription factor candidates from microarray derived gene sets.

Publications

Latent Semantic Indexing of PubMed abstracts for identification of transcription factor candidates from microarray derived gene sets.

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