Chromatin-driven de novo discovery of DNA binding motifs in the human malaria parasite

Elena Y Harris,Nadia Ponts,Stefano Lonardi,Karine G Le Roch

doi:10.1186/1471-2164-12-601

Elena Y Harris, Nadia Ponts + Show 2 more

Open Access

https://doi.org/10.1186/1471-2164-12-601

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Journal: BMC Genomics	Publication Date: Dec 1, 2011
Citations: 34	License type: cc-by

Affiliation: University of California, Riverside

Abstract

BackgroundDespite extensive efforts to discover transcription factors and their binding sites in the human malaria parasite Plasmodium falciparum, only a few transcription factor binding motifs have been experimentally validated to date. As a consequence, gene regulation in P. falciparum is still poorly understood. There is now evidence that the chromatin architecture plays an important role in transcriptional control in malaria.ResultsWe propose a methodology for discovering cis-regulatory elements that uses for the first time exclusively dynamic chromatin remodeling data. Our method employs nucleosome positioning data collected at seven time points during the erythrocytic cycle of P. falciparum to discover putative DNA binding motifs and their transcription factor binding sites along with their associated clusters of target genes. Our approach results in 129 putative binding motifs within the promoter region of known genes. About 75% of those are novel, the remaining being highly similar to experimentally validated binding motifs. About half of the binding motifs reported show statistically significant enrichment in functional gene sets and strong positional bias in the promoter region.ConclusionExperimental results establish the principle that dynamic chromatin remodeling data can be used in lieu of gene expression data to discover binding motifs and their transcription factor binding sites. Our approach can be applied using only dynamic nucleosome positioning data, independent from any knowledge of gene function or expression.

Highlights

Despite extensive efforts to discover transcription factors and their binding sites in the human malaria parasite Plasmodium falciparum, only a few transcription factor binding motifs have been experimentally validated to date
We analyzed the variations of chromatin availability at the loci of two validated transcription factor binding sites (TFBS) that are specific to apicomplexan AP2-related transcription factors [17]
The human malaria parasite has highly skewed nucleotide distribution (~80% of A+T) that together with the fact that over 40% of all genes have no known function makes in silico TFBS discovery challenging

Summary

Introduction

Despite extensive efforts to discover transcription factors and their binding sites in the human malaria parasite Plasmodium falciparum, only a few transcription factor binding motifs have been experimentally validated to date. As a result a variety of algorithms and tools have been developed (see [1] for a review) These methodologies involve obtaining a set of genes which are known to be Algorithms for motif discovery can be enumerative or alignment-based. The discovery of very short or highly degenerated motifs remains statistically challenging These tools have only a limited success when used alone, especially when the ~80% AT-rich genome of the human malaria parasite is considered. Iengar and Joshi [11] combined the strenght of MEME [2], AlignACE [5] and Weeder [3], to identify putative TFBS in promoters of P. falciparum coexpressed genes.

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Conclusion