1,721,262 research outputs found
In Silico prediction of transcription factor binding sites by probabilistic models
Full text linkThe characterization of in silico detected transcription factor binding sites represents a fundamental problem in the field of regulatory gene expression analysis. Several approaches have been proposed to model DNA-protein-interactions, composed by two main classes: qualitative models considering a consensus sequence and quantitative models providing a measure of binding affinity. The latter can be further subdivided in models assuming an independent contribution of the nucleotides forming a potential binding site and more flexible ones implicating a positional interdependence.
In this work the applicability of three probabilistic models to predict transcription factor binding sites has been investigated: (i) the simple position weight matrix (PWM), assuming independence, and two flexible models capturing positional interdependencies represented by a (ii) Chow-Liu Tree and (iii) Ensemble of Trees model. The training and validation of the models on the Mus musculus subset of the UniPROBE database revealed that complex models provide a better predictive power suggesting a high amount of transcription factors binding motifs being affected by positional interdependencies. Additionally, numerous transcription factors were detected, for which the Ensemble of Trees model outperformed both, the Chow-Liu Tree and PWM model.
The UniPROBE-based trained models have been applied in a biological context - the prediction of differential binding profiles in five different ChIP-seq samples, followed by the detection of causative regulatory SNPs. The chosen set-up involved family trio data, meaning genotype data from a family composed of father, mother and daughter, providing internal validation. The models provide strong power to correctly classify true negatives in an independent biological sample, represented by a high specificity. The applied approach to detect causative regulatory SNPs, resulted in a candidate list of 20 SNPs. Those gain strong support by epigenetic markers and both, model-based predicted binding affinity of the comprising binding site and significant p-values, describing the effect of the nucleotide exchange
Impact of chromatin organization on the regulation of vitamin D receptor target genes expression in human prostate cells
Full text linkVitamin D Receptor (VDR) belongs to the superfamily of nuclear receptors that are in total 48 ligand-activated transcription factors that bind to the DNA and are involved in the regulation of gene expression. The active form of vitamin D3, hormone 1α,25-dihydroxyvitaminD3 (1α,25(OH)2D3), is a natural ligand for VDR. The generally described physiological functions of 1α,25(OH)2D3-activated VDR target genes are stimulation of metabolism as well as differentiation and inhibition of inflammation and cellular proliferation. In this study we focus primarily on the target genes of VDR that could potentially have a positive role in cancer prevention. Microarrays were performed of human non-malignant prostate RWPE1 cells after 4 h and 24 h treatment with 100 nM 1α,25(OH)2D3 and among several hundred responsive genes, we identified multiple members of the kallikrein (KLK) gene family as putative primary VDR targets. The KLKs are serine proteases that have been shown to be deregulated in various cancers. The 15 genes in the KLK family cluster together on human chromosome 19 span roughly 270 kB. KLK6 was the most responsive gene (16-fold induction after 4h treatment), followed by its neighboring KLK5, KLK7, KLK8 and KLK9. This effect of 1α,25(OH)2D3 was confirmed by real-time quantitative PCR and loss-of-function experiments. Interestingly, the VDR-mediated induction of the KLK genes was less pronounced in the cancer than in non-malignant prostate cells. In addition, we analyzed the genomic sequence of the KLK cluster in silico and identified a number of putative VDR binding sites (VDREs) as well as putative insulator CTCF binding sites. Chromatin regions containing putative binding sites were analyzed by chromatin immunoprecipitation assays to assess their functionality in RWPE1 cells. Six VDREs were associated with VDR whereas validation of detected CTCF binding sites showed increased occupancy of CTCF upon 1α,25(OH)2D3 stimulation. These results allow describing the changes in chromatin architecture on the KLK locus after VDR activation. Taken together, our study shows that 1α,25(OH)2D3-activated VDR has an impact on the regulation of the whole KLK gene cluster in prostate cells
Identification of KEY transcription factors and their microRNA target genes in adipocytes and macrophages by integration of epigenomic and gene expression data
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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