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An efficient algorithm for improving structure-based prediction of transcription factor binding sites.

ABSTRACT: Gene expression is regulated by transcription factors binding to specific target DNA sites. Understanding how and where transcription factors bind at genome scale represents an essential step toward our understanding of gene regulation networks. Previously we developed a structure-based method for prediction of transcription factor binding sites using an integrative energy function that combines a knowledge-based multibody potential and two atomic energy terms. While the method performs well, it is not computationally efficient due to the exponential increase in the number of binding sequences to be evaluated for longer binding sites. In this paper, we present an efficient pentamer algorithm by splitting DNA binding sequences into overlapping fragments along with a simplified integrative energy function for transcription factor binding site prediction.A DNA binding sequence is split into overlapping pentamers (5 base pairs) for calculating transcription factor-pentamer interaction energy. To combine the results from overlapping pentamer scores, we developed two methods, Kmer-Sum and PWM (Position Weight Matrix) stacking, for full-length binding motif prediction. Our results show that both Kmer-Sum and PWM stacking in the new pentamer approach along with a simplified integrative energy function improved transcription factor binding site prediction accuracy and dramatically reduced computation time, especially for longer binding sites.Our new fragment-based pentamer algorithm and simplified energy function improve both efficiency and accuracy. To our knowledge, this is the first fragment-based method for structure-based transcription factor binding sites prediction.

SUBMITTER: Farrel A

PROVIDER: S-EPMC5514533 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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An efficient algorithm for improving structure-based prediction of transcription factor binding sites.

Farrel Alvin A Guo Jun-Tao JT

BMC bioinformatics 20170717 1

<h4>Background</h4>Gene expression is regulated by transcription factors binding to specific target DNA sites. Understanding how and where transcription factors bind at genome scale represents an essential step toward our understanding of gene regulation networks. Previously we developed a structure-based method for prediction of transcription factor binding sites using an integrative energy function that combines a knowledge-based multibody potential and two atomic energy terms. While the metho ...[more]

PMID: 28715997

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Project description:In computational methods, position weight matrices (PWMs) are commonly applied for transcription factor binding site (TFBS) prediction. Although these matrices are more accurate than simple consensus sequences to predict actual binding sites, they usually produce a large number of false positive (FP) predictions and so are impoverished sources of information. Several studies have employed additional sources of information such as sequence conservation or the vicinity to transcription start sites to distinguish true binding regions from random ones. Recently, the spatial distribution of modified nucleosomes has been shown to be associated with different promoter architectures. These aligned patterns can facilitate DNA accessibility for transcription factors. We hypothesize that using data from these aligned and periodic patterns can improve the performance of binding region prediction. In this study, we propose two effective features, "modified nucleosomes neighboring" and "modified nucleosomes occupancy", to decrease FP in binding site discovery. Based on these features, we designed a logistic regression classifier which estimates the probability of a region as a TFBS. Our model learned each feature based on Sp1 binding sites on Chromosome 1 and was tested on the other chromosomes in human CD4+T cells. In this work, we investigated 21 histone modifications and found that only 8 out of 21 marks are strongly correlated with transcription factor binding regions. To prove that these features are not specific to Sp1, we combined the logistic regression classifier with the PWM, and created a new model to search TFBSs on the genome. We tested the model using transcription factors MAZ, PU.1 and ELF1 and compared the results to those using only the PWM. The results show that our model can predict Transcription factor binding regions more successfully. The relative simplicity of the model and capability of integrating other features make it a superior method for TFBS prediction.

Project description:BackgroundClassically, models of DNA-transcription factor binding sites (TFBSs) have been based on relatively few known instances and have treated them as sites of fixed length using position weight matrices (PWMs). Various extensions to this model have been proposed, most of which take account of dependencies between the bases in the binding sites. However, some transcription factors are known to exhibit some flexibility and bind to DNA in more than one possible physical configuration. In some cases this variation is known to affect the function of binding sites. With the increasing volume of ChIP-seq data available it is now possible to investigate models that incorporate this flexibility. Previous work on variable length models has been constrained by: a focus on specific zinc finger proteins in yeast using restrictive models; a reliance on hand-crafted models for just one transcription factor at a time; and a lack of evaluation on realistically sized data sets.ResultsWe re-analysed binding sites from the TRANSFAC database and found motivating examples where our new variable length model provides a better fit. We analysed several ChIP-seq data sets with a novel motif search algorithm and compared the results to one of the best standard PWM finders and a recently developed alternative method for finding motifs of variable structure. All the methods performed comparably in held-out cross validation tests. Known motifs of variable structure were recovered for p53, Stat5a and Stat5b. In addition our method recovered a novel generalised version of an existing PWM for Sp1 that allows for variable length binding. This motif improved classification performance.ConclusionsWe have presented a new gapped PWM model for variable length DNA binding sites that is not too restrictive nor over-parameterised. Our comparison with existing tools shows that on average it does not have better predictive accuracy than existing methods. However, it does provide more interpretable models of motifs of variable structure that are suitable for follow-up structural studies. To our knowledge, we are the first to apply variable length motif models to eukaryotic ChIP-seq data sets and consequently the first to show their value in this domain. The results include a novel motif for the ubiquitous transcription factor Sp1.

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An efficient algorithm for improving structure-based prediction of transcription factor binding sites.

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An efficient algorithm for improving structure-based prediction of transcription factor binding sites.

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