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BMC Bioinformatics Oct 2009It is known that transcription factors frequently act together to regulate gene expression in eukaryotes. In this paper we describe a computational analysis of...
BACKGROUND
It is known that transcription factors frequently act together to regulate gene expression in eukaryotes. In this paper we describe a computational analysis of transcription factor site dependencies in human, mouse and rat genomes.
RESULTS
Our approach for quantifying tendencies of transcription factor binding sites to co-occur is based on a binding site scoring function which incorporates dependencies between positions, the use of information about the structural class of each transcription factor (major/minor groove binder), and also considered the possible implications of varying GC content of the sequences. Significant tendencies (dependencies) have been detected by non-parametric statistical methodology (permutation tests). Evaluation of obtained results has been performed in several ways: reports from literature (many of the significant dependencies between transcription factors have previously been confirmed experimentally); dependencies between transcription factors are not biased due to similarities in their DNA-binding sites; the number of dependent transcription factors that belong to the same functional and structural class is significantly higher than would be expected by chance; supporting evidence from GO clustering of targeting genes. Based on dependencies between two transcription factor binding sites (second-order dependencies), it is possible to construct higher-order dependencies (networks). Moreover results about transcription factor binding sites dependencies can be used for prediction of groups of dependent transcription factors on a given promoter sequence. Our results, as well as a scanning tool for predicting groups of dependent transcription factors binding sites are available on the Internet.
CONCLUSION
We show that the computational analysis of transcription factor site dependencies is a valuable complement to experimental approaches for discovering transcription regulatory interactions and networks. Scanning promoter sequences with dependent groups of transcription factor binding sites improve the quality of transcription factor predictions.
Topics: Animals; Binding Sites; Computational Biology; DNA; Genome; Humans; Mice; Rats; Sequence Analysis, DNA; Transcription Factors
PubMed: 19835596
DOI: 10.1186/1471-2105-10-339 -
Cell Structure and Function Feb 2023The Gal4/UAS system is a versatile tool to manipulate exogenous gene expression of cells spatially and temporally in many model organisms. Many variations of...
The Gal4/UAS system is a versatile tool to manipulate exogenous gene expression of cells spatially and temporally in many model organisms. Many variations of light-controllable Gal4/UAS system are now available, following the development of photo-activatable (PA) molecular switches and integration of these tools. However, many PA-Gal4 transcription factors have undesired background transcription activities even in dark conditions, and this severely attenuates reliable light-controlled gene expression. Therefore, it is important to develop reliable PA-Gal4 transcription factors with robust light-induced gene expression and limited background activity. By optimization of synthetic PA-Gal4 transcription factors, we have validated configurations of Gal4 DNA biding domain, transcription activation domain and blue light-dependent dimer formation molecule Vivid (VVD), and applied types of transcription activation domains to develop a new PA-Gal4 transcription factor we have named eGAV (enhanced Gal4-VVD transcription factor). Background activity of eGAV in dark conditions was significantly lower than that of hGAVPO, a commonly used PA-Gal4 transcription factor, and maximum light-induced gene expression levels were also improved. Light-controlled gene expression was verified in cultured HEK293T cells with plasmid-transient transfections, and in mouse EpH4 cells with lentivirus vector-mediated transduction. Furthermore, light-controlled eGAV-mediated transcription was confirmed in transfected neural stem cells and progenitors in developing and adult mouse brain and chick spinal cord, and in adult mouse hepatocytes, demonstrating that eGAV can be applied to a wide range of experimental systems and model organisms.Key words: optogenetics, Gal4/UAS system, transcription, gene expression, Vivid.
Topics: Animals; Humans; Mice; Gene Expression Regulation; HEK293 Cells; Mammals; Optogenetics; Transcription Factors; Transcription Factors, General; Cells, Cultured
PubMed: 36529516
DOI: 10.1247/csf.22074 -
Journal of Pharmacological Sciences Dec 2005Differential regulation of gene expression by transcription factors is widely viewed as one of the principal mechanisms guiding development. Although numerous DNA... (Review)
Review
Differential regulation of gene expression by transcription factors is widely viewed as one of the principal mechanisms guiding development. Although numerous DNA binding proteins have been identified in various tissues, the role of individual transcription factors in the differentiation of specific cell groups, such as those populating the inner ear, is just beginning to be elucidated. It is known that transcription factors are induced in response to many signals that lead to cell growth, differentiation, inflammatory responses, the regulation of apoptosis, and neoplastic transformation. There are various transcription factors in the cochlea of the inner ear. These include activator protein-1 and nuclear factor-kappa B, glucocorticoid receptor, and so on. Based on recent reports and our investigation, in this article we review possible functions and expression of these transcription factors.
Topics: Animals; Cochlea; Ear, Inner; Humans; NF-kappa B; Receptors, Glucocorticoid; Transcription Factor AP-1; Transcription Factors
PubMed: 16327216
DOI: 10.1254/jphs.cpj05004x -
BMC Bioinformatics Feb 2021Due to the complexity of the biological systems, the prediction of the potential DNA binding sites for transcription factors remains a difficult problem in computational...
BACKGROUND
Due to the complexity of the biological systems, the prediction of the potential DNA binding sites for transcription factors remains a difficult problem in computational biology. Genomic DNA sequences and experimental results from parallel sequencing provide available information about the affinity and accessibility of genome and are commonly used features in binding sites prediction. The attention mechanism in deep learning has shown its capability to learn long-range dependencies from sequential data, such as sentences and voices. Until now, no study has applied this approach in binding site inference from massively parallel sequencing data. The successful applications of attention mechanism in similar input contexts motivate us to build and test new methods that can accurately determine the binding sites of transcription factors.
RESULTS
In this study, we propose a novel tool (named DeepGRN) for transcription factors binding site prediction based on the combination of two components: single attention module and pairwise attention module. The performance of our methods is evaluated on the ENCODE-DREAM in vivo Transcription Factor Binding Site Prediction Challenge datasets. The results show that DeepGRN achieves higher unified scores in 6 of 13 targets than any of the top four methods in the DREAM challenge. We also demonstrate that the attention weights learned by the model are correlated with potential informative inputs, such as DNase-Seq coverage and motifs, which provide possible explanations for the predictive improvements in DeepGRN.
CONCLUSIONS
DeepGRN can automatically and effectively predict transcription factor binding sites from DNA sequences and DNase-Seq coverage. Furthermore, the visualization techniques we developed for the attention modules help to interpret how critical patterns from different types of input features are recognized by our model.
Topics: Binding Sites; Chromatin; Computational Biology; Neural Networks, Computer; Protein Binding; Transcription Factors
PubMed: 33522898
DOI: 10.1186/s12859-020-03952-1 -
Biochimica Et Biophysica Acta Oct 2012The transcriptional activator β-catenin is a key mediator of the canonical Wnt signaling pathway. β-catenin itself does not bind DNA but functions via interaction with...
The transcriptional activator β-catenin is a key mediator of the canonical Wnt signaling pathway. β-catenin itself does not bind DNA but functions via interaction with T-cell factor (TCF)/lymphoid-enhancing factor (LEF) transcription factors. Thus, in the case of active Wnt signaling, β-catenin, in cooperation with TCF/LEF proteins family, activates the expression of a wide variety of genes. To date, the list of established β-catenin interacting targets is far from complete. In this study, we aimed to establish the interaction between β-catenin and transcription factors that might affect TCF activity. We took advantage of EMSA, using TCF as a probe, to screen oligonucleotides known to bind specific transcription factors that might dislodge or antagonize β-catenin/TCF binding. We found that Sox9 and KLF4 antagonize β-catenin/TCF binding in HEK293, A549, SW480, and T47D cells. This inhibition of TCF binding was concentration-dependent and correlated to the in vitro TCF-luciferase functional assays. Overexpression of Sox9 and KLF4 transcription factors in cancer cells shows a concentration-dependent reduction of TCF-luciferase as well as the TCF-binding activities. In addition, we demonstrated that both Sox9 and KLF4 interact with β-catenin in an immunoprecipitation assay and reduce its binding to TCF4. Together, these results demonstrate that Sox9 and KLF4 transcription factors antagonize β-catenin/TCF in cancer cells.
Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Binding, Competitive; Cell Line, Tumor; HEK293 Cells; Humans; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Luciferases; Oligonucleotides; Protein Binding; SOX9 Transcription Factor; Transcription Factor 4; Transcription Factors; beta Catenin
PubMed: 22766303
DOI: 10.1016/j.bbamcr.2012.06.027 -
Journal of Biochemistry Dec 1997The aryl hydrocarbon receptor (AhR) is widely distributed in vertebrates and is known to be involved in metabolism of xenobiotics including man-made chemicals, most of... (Review)
Review
The aryl hydrocarbon receptor (AhR) is widely distributed in vertebrates and is known to be involved in metabolism of xenobiotics including man-made chemicals, most of which act as a ligand for the receptor, although no endogenous ligand has yet been known. Upon binding a ligand, the receptor is activated to translocate to the nuclei, and during the nuclear translocation process, it is dissociated from the 90 kDa heat shock protein (Hsp90) to form a heterodimer with Arnt (Ah receptor nuclear translocator). The heterodimer complex binds a DNA response element termed xenobiotic responsive element (XRE) localized upstream of the target genes of many drug-metabolizing enzymes including cytochrome P4501A1 and glutathione S-transferase to activate their transcription. Recent cDNA cloning has revealed that the AhR, like Arnt, possesses characteristic structural motifs of basic helix-loop-helix and PAS domains responsible for DNA recognition, heterodimerization, and ligand binding, and functions as a novel receptor-type transcription factor.
Topics: Animals; Humans; Receptors, Aryl Hydrocarbon; Transcription Factors
PubMed: 9498548
DOI: 10.1093/oxfordjournals.jbchem.a021864 -
BMC Bioinformatics Jan 2018De novo prediction of Transcription Factor Binding Sites (TFBS) using computational methods is a difficult task and it is an important problem in Bioinformatics. The...
BACKGROUND
De novo prediction of Transcription Factor Binding Sites (TFBS) using computational methods is a difficult task and it is an important problem in Bioinformatics. The correct recognition of TFBS plays an important role in understanding the mechanisms of gene regulation and helps to develop new drugs.
RESULTS
We here present Memetic Framework for Motif Discovery (MFMD), an algorithm that uses semi-greedy constructive heuristics as a local optimizer. In addition, we used a hybridization of the classic genetic algorithm as a global optimizer to refine the solutions initially found. MFMD can find and classify overrepresented patterns in DNA sequences and predict their respective initial positions. MFMD performance was assessed using ChIP-seq data retrieved from the JASPAR site, promoter sequences extracted from the ABS site, and artificially generated synthetic data. The MFMD was evaluated and compared with well-known approaches in the literature, called MEME and Gibbs Motif Sampler, achieving a higher f-score in the most datasets used in this work.
CONCLUSIONS
We have developed an approach for detecting motifs in biopolymers sequences. MFMD is a freely available software that can be promising as an alternative to the development of new tools for de novo motif discovery. Its open-source software can be downloaded at https://github.com/jadermcg/mfmd .
Topics: Algorithms; Base Sequence; Binding Sites; Internet; Transcription Factors; User-Computer Interface
PubMed: 29298679
DOI: 10.1186/s12859-017-2005-1 -
CNS Neuroscience & Therapeutics Sep 2020Astrogliosis and glial scar formation following spinal cord injury (SCI) are viewed as major obstacles that hinder axonal regeneration and functional recovery....
INTRODUCTION
Astrogliosis and glial scar formation following spinal cord injury (SCI) are viewed as major obstacles that hinder axonal regeneration and functional recovery. Regulating the glial scar and axonal regeneration in the lesion site is important for treating SCI.
AIMS
Considering the important role of astrocyte in glial scar formation and subsequent axonal regeneration, we intended to investigate the effect of the transcription factors OCT4 and KLF4 on astrocyte and the underlying mechanism after spinal cord contusion injury in transgenic mice.
RESULTS
Western blotting, q-PCR, immunofluorescence, and functional evaluation suggested that glial fibrillary acidic protein (GFAP) expression decreased in the lesion area, the porosity of the scar increased, and remyelination enhanced. Mice overexpressing the transcription factors OCT4 and KLF4 had higher Basso Mouse Scale scores than did the control mice. Moreover, using immunofluorescence and Western blotting, we discovered that some astrocytes expressed nestin and sox2 protein, suggesting that these astrocytes were reprogrammed into neural stem cell-like cells. Furthermore, a cell scratch assay showed that the migration ability of the astrocytes was significantly inhibited in the presence of the transcription factors OCT4 and KLF4. In addition, we demonstrated that the Hippo/Yap pathway was activated after these two transcription factors overexpressed in astrocytes.
CONCLUSIONS
In summary, these results suggest that overexpression of the transcription factors OCT4 and KLF4 could induce astrocyte reprogramming, which subsequently improves remyelination and functional recovery after SCI.
Topics: Animals; Animals, Newborn; Astrocytes; Cells, Cultured; Gene Expression; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Mice; Mice, Inbred C57BL; Mice, Transgenic; Octamer Transcription Factor-3; Recovery of Function; Spinal Cord Injuries; Transcription Factors
PubMed: 32449258
DOI: 10.1111/cns.13390 -
Journal of Neurochemistry May 2023Cells possess intrinsic features that are inheritable via epigenetic regulation, such as DNA methylation and histone modification. These inheritable features maintain a...
Cells possess intrinsic features that are inheritable via epigenetic regulation, such as DNA methylation and histone modification. These inheritable features maintain a unique gene expression pattern, underlying cellular memory. Because of the degradation or displacement of mitotic chromosomes, most transcription factors do not contribute to cellular memory. However, accumulating in vitro evidence indicates that some transcription factors can be retained in mitotic chromosomes called as bookmarking. Such transcription factors may contribute to a novel third mechanism of cellular memory. Since most findings of transcription factor bookmarking have been reported in vitro, little is currently known in vivo. In the neural tube of mouse embryos, we discovered that OLIG2, a basic helix loop helix (bHLH) transcription factor that regulates proliferation of neural progenitors and the cell fate of motoneurons and oligodendrocytes, binds to chromatin through every cell cycle including M-phase. OLIG2 chromosomal localization coincides with mitotic cell features such as the phosphorylation of histone H3, KI67, and nuclear membrane breakdown. Chromosomal localization of OLIG2 is regulated by an N-terminus triple serine motif. Photobleaching analysis revealed slow OLIG2 mobility, suggesting a high affinity of OLIG2 to DNA. In Olig2 N-terminal deletion mutant mice, motoneurons and oligodendrocyte progenitor numbers are reduced in the neural tube, suggesting that the bookmarking regulatory domain is important for OLIG2 function. We conclude that OLIG2 is a de novo in vivo bookmarking transcription factor. Our results demonstrate the presence of in vivo bookmarking in a living organism and illustrate a novel function of transcription factors.
Topics: Mice; Animals; Transcription Factors; Epigenesis, Genetic; Neural Tube; Nerve Tissue Proteins; Oligodendrocyte Transcription Factor 2; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Oligodendroglia
PubMed: 36547371
DOI: 10.1111/jnc.15746 -
Developmental Biology Dec 1995The production of transcription factor isoforms by developmentally regulated alternative splicing of pre-mRNAs is a widespread phenomenon. Frequently, differences in... (Review)
Review
The production of transcription factor isoforms by developmentally regulated alternative splicing of pre-mRNAs is a widespread phenomenon. Frequently, differences in biochemical function among the isoforms can be predicted from sequence analysis, and in many instances such differences have been demonstrated in vitro or in cultured cells. A great variety of strategies for functional diversification can be classified into three main types: modulation of DNA binding specificity or affinity, production of activators and antagonists from the same gene, and modulation of dimerization properties. Despite obvious implications in many cases, the actual developmental consequences are understood only in a few instances. The roles inferred from these examples are diverse, ranging from developmental switches that have profound effects on pathways of differentiation to mechanisms that may optimize or fine-tune transcription factor function in different contexts.
Topics: Alternative Splicing; Animals; Gene Expression Regulation, Developmental; Humans; RNA; Transcription Factors
PubMed: 8612959
DOI: 10.1006/dbio.1995.8050