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Concerted bioinformatic analysis of the genome-scale blood transcription factor compendium reveals new control mechanisms.

ABSTRACT: Transcription factors play a key role in the development of a disease. ChIP-sequencing has become a preferred technique to investigate genome-wide binding patterns of transcription factors in vivo. Although this technology has led to many important discoveries, the rapidly increasing number of publicly available ChIP-sequencing datasets still remains a largely unexplored resource. Using a compendium of 144 publicly available murine ChIP-sequencing datasets in blood, we show that systematic bioinformatic analysis can unravel diverse aspects of transcription regulation; from genome-wide binding preferences, finding regulatory partners and assembling regulatory complexes, to identifying novel functions of transcription factors and investigating transcription dynamics during development.

SUBMITTER: Joshi A

PROVIDER: S-EPMC4263230 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Concerted bioinformatic analysis of the genome-scale blood transcription factor compendium reveals new control mechanisms.

Joshi Anagha A Gottgens Berthold B

Molecular bioSystems 20141101 11

Transcription factors play a key role in the development of a disease. ChIP-sequencing has become a preferred technique to investigate genome-wide binding patterns of transcription factors in vivo. Although this technology has led to many important discoveries, the rapidly increasing number of publicly available ChIP-sequencing datasets still remains a largely unexplored resource. Using a compendium of 144 publicly available murine ChIP-sequencing datasets in blood, we show that systematic bioin ...[more]

PMID: 25133983

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Project description:BackgroundTranscription factors (TF) regulate expression by binding to specific DNA sequences. A binding event is functional when it affects gene expression. Functionality of a binding site is reflected in conservation of the binding sequence during evolution and in over represented binding in gene groups with coherent biological functions. Functionality is governed by several parameters such as the TF-DNA binding strength, distance of the binding site from the transcription start site (TSS), DNA packing, and more. Understanding how these parameters control functionality of different TFs in different biological contexts is a must for identifying functional TF binding sites and for understanding regulation of transcription.Methodology/principal findingsWe introduce a novel method to screen the promoters of a set of genes with shared biological function (obtained from the functional Gene Ontology (GO) classification) against a precompiled library of motifs, and find those motifs which are statistically over-represented in the gene set. More than 8,000 human (and 23,000 mouse) genes, were assigned to one of 134 GO sets. Their promoters were searched (from 200 bp downstream to 1,000 bp upstream the TSS) for 414 known DNA motifs. We optimized the sequence similarity score threshold, independently for every location window, taking into account nucleotide heterogeneity along the promoters of the target genes. The method, combined with binding sequence and location conservation between human and mouse, identifies with high probability functional binding sites for groups of functionally-related genes. We found many location-sensitive functional binding events and showed that they clustered close to the TSS. Our method and findings were tested experimentally.Conclusions/significanceWe identified reliably functional TF binding sites. This is an essential step towards constructing regulatory networks. The promoter region proximal to the TSS is of central importance for regulation of transcription in human and mouse, just as it is in bacteria and yeast.

Project description:BACKGROUND:Cowpea (Vigna unguiculata (L.) Walp.) is the most important food and forage legume in the semi-arid tropics of sub-Saharan Africa where approximately 80% of worldwide production takes place primarily on low-input, subsistence farm sites. Among the major goals of cowpea breeding and improvement programs are the rapid manipulation of agronomic traits for seed size and quality and improved resistance to abiotic and biotic stresses to enhance productivity. Knowing the suite of transcription factors (TFs) and transcriptionally active proteins (TAPs) that control various critical plant cellular processes would contribute tremendously to these improvement aims. RESULTS:We used a computational approach that employed three different predictive pipelines to data mine the cowpea genome and identified over 4400 genes representing 136 different TF and TAP families. We compare the information content of cowpea to two evolutionarily close species common bean (Phaseolus vulgaris), and soybean (Glycine max) to gauge the relative informational content. Our data indicate that correcting for genome size cowpea has fewer TF and TAP genes than common bean (4408 / 5291) and soybean (4408/ 11,065). Members of the GROWTH-REGULATING FACTOR (GRF) and Auxin/indole-3-acetic acid (Aux/IAA) gene families appear to be over-represented in the genome relative to common bean and soybean, whereas members of the MADS (Minichromosome maintenance deficient 1 (MCM1), AGAMOUS, DEFICIENS, and serum response factor (SRF)) and C2C2-YABBY appear to be under-represented. Analysis of the AP2-EREBP APETALA2-Ethylene Responsive Element Binding Protein (AP2-EREBP), NAC (NAM (no apical meristem), ATAF1, 2 (Arabidopsis transcription activation factor), CUC (cup-shaped cotyledon)), and WRKY families, known to be important in defense signaling, revealed changes and phylogenetic rearrangements relative to common bean and soybean that suggest these groups may have evolved different functions. CONCLUSIONS:The availability of detailed information on the coding capacity of the cowpea genome and in particular the various TF and TAP gene families will facilitate future comparative analysis and development of strategies for controlling growth, differentiation, and abiotic and biotic stress resistances of cowpea.

Dataset Information

Concerted bioinformatic analysis of the genome-scale blood transcription factor compendium reveals new control mechanisms.

Publications

Concerted bioinformatic analysis of the genome-scale blood transcription factor compendium reveals new control mechanisms.

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