DISPOM: A DISCRIMINATIVE DE-NOVO MOTIF DISCOVERY TOOL BASED ON THE JSTACS LIBRARY

2013 ◽  
Vol 11 (01) ◽  
pp. 1340006 ◽  
Author(s):  
JAN GRAU ◽  
JENS KEILWAGEN ◽  
ANDRÉ GOHR ◽  
IVAN A. PAPONOV ◽  
STEFAN POSCH ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Binding Sites ◽  
Motif Discovery ◽  
Binding Proteins ◽  
Target Genes ◽  
De Novo ◽  
Specific Binding ◽  
Dna Binding Proteins ◽  
De Novo Motif Discovery

DNA-binding proteins are a main component of gene regulation as they activate or repress gene expression by binding to specific binding sites in target regions of genomic DNA. However, de-novo discovery of these binding sites in target regions obtained by wet-lab experiments is a challenging problem in computational biology, which has not yet been solved satisfactorily. Here, we present a detailed description and analysis of the de-novo motif discovery tool Dispom, which has been developed for finding binding sites of DNA-binding proteins that are differentially abundant in a set of target regions compared to a set of control regions. Two additional features of Dispom are its capability of modeling positional preferences of binding sites and adjusting the length of the motif in the learning process. Dispom yields an increased prediction accuracy compared to existing tools for de-novo motif discovery, suggesting that the combination of searching for differentially abundant motifs, inferring their positional distributions, and adjusting the motif lengths is beneficial for de-novo motif discovery. When applying Dispom to promoters of auxin-responsive genes and those of ABI3 target genes from Arabidopsis thaliana, we identify relevant binding motifs with pronounced positional distributions. These results suggest that learning motifs, their positional distributions, and their lengths by a discriminative learning principle may aid motif discovery from ChIP-chip and gene expression data. We make Dispom freely available as part of Jstacs, an open-source Java library that is tailored to statistical sequence analysis. To facilitate extensions of Dispom, we describe its implementation using Jstacs in this manuscript. In addition, we provide a stand-alone application of Dispom at http://www.jstacs.de/index.php/Dispom for instant use.

scholarly journals EPEN-41. C11orf95-RELA FUSION REGULATES ABERRANT GENE EXPRESSION THROUGH THE UNIQUE GENOMIC BINDING SITES FOR EPENDYMOMA FORMATION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii316-iii316
Author(s):  
Tatsuya Ozawa ◽  
Syuzo Kaneko ◽  
Mutsumi Takadera ◽  
Eric Holland ◽  
Ryuji Hamamoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Binding Sites ◽  
Motif Discovery ◽  
Target Genes ◽  
Cultured Cells ◽  
De Novo ◽  
Binding Motif ◽  
Aberrant Gene Expression ◽  
Aberrant Gene

Abstract A majority of supratentorial ependymoma is associated with recurrent C11orf95-RELA fusion (RELAFUS). The presence of RELA as one component of the RELAFUS leads to the suggestion that NF-kB activity is involved in the ependymoma formation, thus being a viable therapeutic target in these tumors. However, the oncogenic role of another C11orf95 component in the tumorigenesis is not still determined. In this study, to clarify the molecular mechanism underlying tumorigenesis of RELAFUS, we performed RELAFUS-ChIP-Seq analysis in cultured cells expressing the RELAFUS protein. Genomic profiling of RELAFUS binding sites pinpointed the transcriptional target genes directly regulated by RELAFUS. We then identified a unique DNA binding motif of the RELAFUS different from the canonical NF-kB motif in de novo motif discovery analysis. Significant responsiveness of RELAFUS but not RELA to the motif was confirmed in the reporter assay. An N-terminal portion of C11orf95 was sufficient to localize in the nucleus and recognizes the unique motif. Interestingly, the RELAFUS peaks concomitant with the unique motif were identified around the transcription start site in the RELAFUS target genes as previously reported. These observations suggested that C11orf95 might have served as a key determinant for the DNA binding sites of RELAFUS, thereby induced aberrant gene expression necessary for ependymoma formation. Our results will give insights into the development of new ependymoma therapy.

scholarly journals Genome wide screens in yeast to identify potential binding sites and target genes of DNA-binding proteins

2007 ◽  
Vol 36 (1) ◽  
pp. e8-e8 ◽  
Author(s):  
Jue Zeng ◽  
Jizhou Yan ◽  
Ting Wang ◽  
Deborah Mosbrook-Davis ◽  
Kyle T. Dolan ◽  
...  
Keyword(s):  
Dna Binding ◽  
Binding Sites ◽  
Binding Proteins ◽  
Target Genes ◽  
Dna Binding Proteins ◽  
Genome Wide ◽  
Potential Binding

scholarly journals Genetic and epigenetic control of the spatial organization of the genome

2017 ◽  
Vol 28 (3) ◽  
pp. 364-369 ◽  
Author(s):  
Jason Brickner
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Chromatin Structure ◽  
Binding Sites ◽  
Spatial Organization ◽  
Binding Proteins ◽  
Dna Binding Proteins ◽  
Adaptive Function ◽  
Nuclear Structures ◽  
Eukaryotic Genomes

Eukaryotic genomes are spatially organized within the nucleus by chromosome folding, interchromosomal contacts, and interaction with nuclear structures. This spatial organization is observed in diverse organisms and both reflects and contributes to gene expression and differentiation. This leads to the notion that the arrangement of the genome within the nucleus has been shaped and conserved through evolutionary processes and likely plays an adaptive function. Both DNA-binding proteins and changes in chromatin structure influence the positioning of genes and larger domains within the nucleus. This suggests that the spatial organization of the genome can be genetically encoded by binding sites for DNA-binding proteins and can also involve changes in chromatin structure, potentially through nongenetic mechanisms. Here I briefly discuss the results that support these ideas and their implications for how genomes encode spatial organization.

De Novo Motif Prediction Using the Fireworks Algorithm

Biotechnology ◽  
2019 ◽  
pp. 1069-1085
Author(s):  
Andrei Lihu ◽  
Ștefan Holban
Keyword(s):  
Gene Expression ◽  
Motif Discovery ◽  
De Novo ◽  
Fireworks Algorithm ◽  
Regulatory Processes ◽  
Motif Prediction ◽  
Leibler Divergence ◽  
De Novo Motif Discovery ◽  
Low Performance ◽  
Motif Finding Algorithm

De novo motif discovery is essential in understanding the cis-regulatory processes that play a role in gene expression. Finding unknown patterns of unknown lengths in massive amounts of data has long been a major challenge in computational biology. Because algorithms for motif prediction have always suffered of low performance issues, there is a constant effort to find better techniques. Evolutionary methods, including swarm intelligence algorithms, have been applied with limited success for motif prediction. However, recently developed methods, such as the Fireworks Algorithm (FWA) which simulates the explosion process of fireworks, may show better prospects. This paper describes a motif finding algorithm based on FWA that maximizes the Kullback-Leibler divergence between candidate solutions and the background noise. Following the terminology of FWA's framework, the candidate motifs are fireworks that generate additional sparks (i.e. derived motifs) in their neighborhood. During the iterations, better sparks can replace the fireworks, as the Fireworks Motif Finder (FW-MF) assumes a one occurrence per sequence mode. The results obtained on a standard benchmark for promoter analysis show that our proof of concept is promising.

The discovery of zinc fingers and their development for practical applications in gene regulation and genome manipulation

2010 ◽  
Vol 43 (1) ◽  
pp. 1-21 ◽  
Author(s):  
Aaron Klug
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Zinc Finger ◽  
Binding Proteins ◽  
Zinc Fingers ◽  
Dna Binding Proteins ◽  
Functional Domains ◽  
Control Of Gene Expression ◽  
Activation Domains ◽  
Finger Peptides

AbstractA long-standing goal of molecular biologists has been to construct DNA-binding proteins for the control of gene expression. The classical Cys2His2 (C2H2) zinc finger design is ideally suited for such purposes. Discriminating between closely related DNA sequences both in vitro and in vivo, this naturally occurring design was adopted for engineering zinc finger proteins (ZFPs) to target genes specifically.Zinc fingers were discovered in 1985, arising from the interpretation of our biochemical studies on the interaction of the Xenopus protein transcription factor IIIA (TFIIIA) with 5S RNA. Subsequent structural studies revealed its three-dimensional structure and its interaction with DNA. Each finger constitutes a self-contained domain stabilized by a zinc (Zn) ion ligated to a pair of cysteines and a pair of histidines and also by an inner structural hydrophobic core. This discovery showed not only a new protein fold but also a novel principle of DNA recognition. Whereas other DNA-binding proteins generally make use of the 2-fold symmetry of the double helix, functioning as homo- or heterodimers, zinc fingers can be linked linearly in tandem to recognize nucleic acid sequences of varying lengths. This modular design offers a large number of combinatorial possibilities for the specific recognition of DNA (or RNA). It is therefore not surprising that the zinc finger is found widespread in nature, including 3% of the genes of the human genome.The zinc finger design can be used to construct DNA-binding proteins for specific intervention in gene expression. By fusing selected zinc finger peptides to repression or activation domains, genes can be selectively switched off or on by targeting the peptide to the desired gene target. It was also suggested that by combining an appropriate zinc finger peptide with other effector or functional domains, e.g. from nucleases or integrases to form chimaeric proteins, genomes could be modified or manipulated.The first example of the power of the method was published in 1994 when a three-finger protein was constructed to block the expression of a human oncogene transformed into a mouse cell line. The same paper also described how a reporter gene was activated by targeting an inserted 9-base pair (bp) sequence, which acts as the promoter. Thus, by fusing zinc finger peptides to repression or activation domains, genes can be selectively switched off or on. It was also suggested that, by combining zinc fingers with other effector or functional domains, e.g. from nucleases or integrases, to form chimaeric proteins, genomes could be manipulated or modified.Several applications of such engineered ZFPs are described here, including some of therapeutic importance, and also their adaptation for breeding improved crop plants.

scholarly journals Integrating sequence and gene expression information predicts genome-wide DNA-binding proteins and suggests a cooperative mechanism

2017 ◽  
Vol 46 (1) ◽  
pp. 54-70 ◽  
Author(s):  
Shandar Ahmad ◽  
Philip Prathipati ◽  
Lokesh P Tripathi ◽  
Yi-An Chen ◽  
Ajay Arya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Binding Proteins ◽  
Dna Binding Proteins ◽  
Gene Expression Information ◽  
Genome Wide
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