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Transcription factor map alignment of promoter regions.

ABSTRACT: We address the problem of comparing and characterizing the promoter regions of genes with similar expression patterns. This remains a challenging problem in sequence analysis, because often the promoter regions of co-expressed genes do not show discernible sequence conservation. In our approach, thus, we have not directly compared the nucleotide sequence of promoters. Instead, we have obtained predictions of transcription factor binding sites, annotated the predicted sites with the labels of the corresponding binding factors, and aligned the resulting sequences of labels--to which we refer here as transcription factor maps (TF-maps). To obtain the global pairwise alignment of two TF-maps, we have adapted an algorithm initially developed to align restriction enzyme maps. We have optimized the parameters of the algorithm in a small, but well-curated, collection of human-mouse orthologous gene pairs. Results in this dataset, as well as in an independent much larger dataset from the CISRED database, indicate that TF-map alignments are able to uncover conserved regulatory elements, which cannot be detected by the typical sequence alignments.

SUBMITTER: Blanco E

PROVIDER: S-EPMC1464811 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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Transcription factor map alignment of promoter regions.

Blanco Enrique E Messeguer Xavier X Smith Temple F TF Guigó Roderic R

PLoS computational biology 20060526 5

We address the problem of comparing and characterizing the promoter regions of genes with similar expression patterns. This remains a challenging problem in sequence analysis, because often the promoter regions of co-expressed genes do not show discernible sequence conservation. In our approach, thus, we have not directly compared the nucleotide sequence of promoters. Instead, we have obtained predictions of transcription factor binding sites, annotated the predicted sites with the labels of the ...[more]

PMID: 16733547

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Project description:MotivationThe identification of transcription factor (TF) binding sites and the regulatory circuitry that they define is currently an area of intense research. Data from whole-genome chromatin immunoprecipitation (ChIP-chip), whole-genome expression microarrays, and sequencing of multiple closely related genomes have all proven useful. By and large, existing methods treat the interpretation of functional data as a classification problem (between bound and unbound DNA), and the analysis of comparative data as a problem of local alignment (to recover phylogenetic footprints of presumably functional elements). Both of these approaches suffer from the inability to model and detect low-affinity binding sites, which have recently been shown to be abundant and functional.ResultsWe have developed a method that discovers functional regulatory targets of TFs by predicting the total affinity of each promoter for those factors and then comparing that affinity across orthologous promoters in closely related species. At each promoter, we consider the minimum affinity among orthologs to be the fraction of the affinity that is functional. Because we calculate the affinity of the entire promoter, our method is independent of local alignment. By comparing with functional annotation information and gene expression data in Saccharomyces cerevisiae, we have validated that this biophysically motivated use of evolutionary conservation gives rise to dramatic improvement in prediction of regulatory connectivity and factor-factor interactions compared to the use of a single genome. We propose novel biological functions for several yeast TFs, including the factors Snt2 and Stb4, for which no function has been reported. Our affinity-based approach towards comparative genomics may allow a more quantitative analysis of the principles governing the evolution of non-coding DNA.AvailabilityThe MatrixREDUCE software package is available from http://www.bussemakerlab.org/software/MatrixREDUCE.Supplementary informationSupplementary data are available at Bioinformatics online.

Project description:BackgroundMyxococcus xanthus is a bacterium that undergoes multicellular development when starved. Cells move to aggregation centers and form fruiting bodies in which cells differentiate into dormant spores. MrpC appears to directly activate transcription of fruA, which also codes for a transcription factor. Both MrpC and FruA are crucial for aggregation and sporulation. The two proteins bind cooperatively in promoter regions of some developmental genes.ResultsChromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) and bioinformatic analysis of cells that had formed nascent fruiting bodies revealed 1608 putative MrpC binding sites. These sites included several known to bind MrpC and they were preferentially distributed in likely promoter regions, especially those of genes up-regulated during development. The up-regulated genes include 22 coding for protein kinases. Some of these are known to be directly involved in fruiting body formation and several negatively regulate MrpC accumulation. Our results also implicate MrpC as a direct activator or repressor of genes coding for several transcription factors known to be important for development, for a major spore protein and several proteins important for spore formation, for proteins involved in extracellular A- and C-signaling, and intracellular ppGpp-signaling during development, and for proteins that control the fate of other proteins or play a role in motility. We found that the putative MrpC binding sites revealed by ChIP-seq are enriched for DNA sequences that strongly resemble a consensus sequence for MrpC binding proposed previously. MrpC2, an N-terminally truncated form of MrpC, bound to DNA sequences matching the consensus in all 11 cases tested. Using longer DNA segments containing 15 of the putative MrpC binding sites from our ChIP-seq analysis as probes in electrophoretic mobility shift assays, evidence for one or more MrpC2 binding site was observed in all cases and evidence for cooperative binding of MrpC2 and FruA was seen in 13 cases.ConclusionsWe conclude that MrpC and MrpC2 bind to promoter regions of hundreds of developmentally-regulated genes in M. xanthus, in many cases cooperatively with FruA. This binding very likely up-regulates protein kinases, and up- or down-regulates other proteins that profoundly influence the developmental process.

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Transcription factor map alignment of promoter regions.

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Transcription factor map alignment of promoter regions.

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