A computational evaluation of over-representation of regulatory motifs in the promoter regions of differentially expressed genes

BACKGROUND: Observed co-expression of a group of genes is frequently attributed to co-regulation by shared transcription factors. This assumption has led to the hypothesis that promoters of co-expressed genes should share common regulatory motifs, which forms the basis for numerous computational tools that search for these motifs. While frequently explored for yeast, the validity of the underlying hypothesis has not been assessed systematically in mammals. This demonstrates the need for a systematic and quantitative evaluation to what degree co-expressed genes share over-represented motifs for mammals. RESULTS: We identified 33 experiments for human and mouse in the ArrayExpress Database where transcription factors were manipulated and which exhibited a significant number of differentially expressed genes. We checked for over-representation of transcription factor binding sites in up- or down-regulated genes using the over-representation analysis tool oPOSSUM. In 25 out of 33 experiments, this procedure identified the binding matrices of the affected transcription factors. We also carried out de novo prediction of regulatory motifs shared by differentially expressed genes. Again, the detected motifs shared significant similarity with the matrices of the affected transcription factors. CONCLUSIONS: Our results support the claim that functional regulatory motifs are over-represented in sets of differentially expressed genes and that they can be detected with computational methods

Discovery, validation, and genetic dissection of transcription factor binding sites by comparative and functional genomics

Completing the annotation of a genome sequence requires identifying the regulatory sequences that control gene expression. To identify these sequences, we developed an algorithm that searches for short, conserved sequence motifs in the genomes of related species. The method is effective in finding motifs de novo and for refining known regulatory motifs in Saccharomyces cerevisiae. We tested one novel motif prediction of the algorithm and found it to be the binding site of Stp2; it is significantly different from the previously predicted Stp2 binding site. We show that Stp2 physically interacts with this sequence motif, and that stp2 mutations affect the expression of genes associated with the motif. We demonstrate that the Stp2 binding site also interacts genetically with Stp1, a regulator of amino acid permease genes and, with Sfp1, a key regulator of cell growth. These results illuminate an important transcriptional circuit that regulates cell growth through external nutrient uptake

Brain Magnetic Resolution Imaging to Diagnose Bing-Neel Syndrome

Radiologic findings of Bing-Neel syndrome, which is an extremely uncommon complication resulting from malignant lymphocyte infiltration into the central nervous system (CNS) in patients with Waldenström's macroglobulinemia (WM), have been infrequently reported due to extreme rarity of the case. A 75-year-old man with WM presented at a neurology clinic with progressive gait and memory disturbances, and dysarthria of 2 months duration. Cerebrospinal fluid and serum protein electrophoresis and immunofixation electrophoresis showed IgM kappa-type monoclonal gammopathy. Brain magnetic resonance imaging revealed multifocal, hyperintense lesions on T2 weighted-images. Brain diffusion-weighted imaging (DWI) demonstrated hyperintensities in cerebral and cerebellar lesions that appeared isointense on apparent diffusion coefficient maps, which were compatible with vasogenic edema. Although histologic analysis is a confirmative study to prove direct cell infiltration into the brain, brain MRI with DWI may be a good supportive study to diagnose Bing-Neel syndrome

Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event

Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age. The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure. Here, we use array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination, showing the simultaneous transfer of multiple and often large (up to at least 44 kb) DNA fragments. We show that one such new strain quickly became established, spreading from east to west across the United States. These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases. © 2012 Nature America, Inc. All rights reserved