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Results for “regulatory element transcripts”

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PubMed2006

Identification of proteins immunologically related to interferon regulatory factor-1 that bind with interferon regulatory factor element.

Interferon regulatory factor (IRF)-1 expression was surveyed in nontransformed and oncogene-transformed mouse fibroblasts, using Western immunoblot with an IRF-1-specific antiserum, to examine possible differences resulting from cellular transformation. Ten additional proteins that reacted with the IRF-1 antibody and that underwent specific competition by peptide antigen were observed in extracts of both nontransformed and oncogene-transformed cell lines. Cross-reacting proteins were also observed in mouse macrophage extracts. Protein was captured from fibroblast nuclear extracts, using oligonucleotides representing IRF-binding sequences linked to magnetic beads. Captured proteins were eluted and analyzed by immunoblot with anti-IRF-1. Along with 43-kDa IRF-1, 4 of the 7 nuclearly located cross-reacting proteins (97, 90, 66, and 33 kDa) were found to complex with the IRF binding element. These proteins, with an epitope in common with the IRF-1 C-terminal region and IRF element DNA sequence-binding capability, may represent new members of the IRF family.

Animals↗

PubMed2006

Dynamical analysis of a generic Boolean model for the control of the mammalian cell cycle.

MOTIVATION: To understand the behaviour of complex biological regulatory networks, a proper integration of molecular data into a full-fledge formal dynamical model is ultimately required. As most available data on regulatory interactions are qualitative, logical modelling offers an interesting framework to delineate the main dynamical properties of the underlying networks. RESULTS: Transposing a generic model of the core network controlling the mammalian cell cycle into the logical framework, we compare different strategies to explore its dynamical properties. In particular, we assess the respective advantages and limits of synchronous versus asynchronous updating assumptions to delineate the asymptotical behaviour of regulatory networks. Furthermore, we propose several intermediate strategies to optimize the computation of asymptotical properties depending on available knowledge. AVAILABILITY: The mammalian cell cycle model is available in a dedicated XML format (GINML) on our website, along with our logical simulation software GINsim (http://gin.univ-mrs.fr/GINsim). Higher resolution state transitions graphs are also found on this web site (Model Repository page).

Animals↗

PubMed2006

A sequence-based filtering method for ncRNA identification and its application to searching for riboswitch elements.

MOTIVATION: Recent studies have uncovered an "RNA world", in which non coding RNA (ncRNA) sequences play a central role in the regulation of gene expression. Computational studies on ncRNA have been directed toward developing detection methods for ncRNAs. State-of-the-art methods for the problem, like covariance models, suffer from high computational cost, underscoring the need for efficient filtering approaches that can identify promising sequence segments and speedup the detection process. RESULTS: In this paper we make several contributions toward this goal. First, we formalize the concept of a filter and provide figures of merit that allow comparison between filters. Second, we design efficient sequence based filters that dominate the current state-of-the-art HMM filters. Third, we provide a new formulation of the covariance model that allows speeding up RNA alignment. We demonstrate the power of our approach on both synthetic data and real bacterial genomes. We then apply our algorithm to the detection of novel riboswitch elements from the whole bacterial and archaeal genomes. Our results point to a number of novel riboswitch candidates, and include genomes that were not previously known to contain riboswitches. AVAILABILITY: The program is available upon request from the authors.

Algorithms↗

PubMed2006

MotifCut: regulatory motifs finding with maximum density subgraphs.

MOTIVATION: DNA motif finding is one of the core problems in computational biology, for which several probabilistic and discrete approaches have been developed. Most existing methods formulate motif finding as an intractable optimization problem and rely either on expectation maximization (EM) or on local heuristic searches. Another challenge is the choice of motif model: simpler models such as the position-specific scoring matrix (PSSM) impose biologically unrealistic assumptions such as independence of the motif positions, while more involved models are harder to parametrize and learn. RESULTS: We present MotifCut, a graph-theoretic approach to motif finding leading to a convex optimization problem with a polynomial time solution. We build a graph where the vertices represent all k-mers in the input sequences, and edges represent pairwise k-mer similarity. In this graph, we search for a motif as the maximum density subgraph, which is a set of k-mers that exhibit a large number of pairwise similarities. Our formulation does not make strong assumptions regarding the structure of the motif and in practice both motifs that fit well the PSSM model, and those that exhibit strong dependencies between position pairs are found as dense subgraphs. We benchmark MotifCut on both synthetic and real yeast motifs, and find that it compares favorably to existing popular methods. The ability of MotifCut to detect motifs appears to scale well with increasing input size. Moreover, the motifs we discover are different from those discovered by the other methods. AVAILABILITY: MotifCut server and other materials can be found at motifcut.stanford.edu.

Algorithms↗

PubMed2006

Apples to apples: improving the performance of motif finders and their significance analysis in the Twilight Zone.

MOTIVATION: Effective algorithms for finding relatively weak motifs are an important practical necessity while scanning long DNA sequences for regulatory elements. The success of such an algorithm hinges on the ability of its scoring function combined with a significance analysis test to discern real motifs from random noise. RESULTS: In the first half of the paper we show that the paradigm of relying on entropy scores and their E-values can lead to undesirable results when searching for weak motifs and we offer alternate approaches to analyzing the significance of motifs. In the second half of the paper we reintroduce a scoring function and present a motif-finder that optimizes it that are more effective in finding relatively weak motifs than other tools. AVAILABILITY: The GibbsILR motif finder is available at http://www.cs.cornell.edu/~keich.

Algorithms↗

PubMed2006

Adding sequence context to a Markov background model improves the identification of regulatory elements.

MOTIVATION: Many computational methods for identifying regulatory elements use a likelihood ratio between motif and background models. Often, the methods use a background model of independent bases. At least two different Markov background models have been proposed with the aim of increasing the accuracy of predicting regulatory elements. Both Markov background models suffer theoretical drawbacks, so this article develops a third, context-dependent Markov background model from fundamental statistical principles. RESULTS: Datasets containing known regulatory elements in eukaryotes provided a basis for comparing the predictive accuracies of the different background models. Non-parametric statistical tests indicated that Markov models of order 3 constituted a statistically significant improvement over the background model of independent bases. Our model performed slightly better than the previous Markov background models. We also found that for discriminating between the predictive accuracies of competing background models, the correlation coefficient is a more sensitive measure than the performance coefficient. AVAILABILITY: Our C++ program is available at ftp://ftp.ncbi.nih.gov/pub/spouge/papers/archive/AGLAM/2006-07-19

Algorithms↗

PubMed2006

An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers.

Numerous disease-associated point mutations exert their effects by disrupting the activity of exonic splicing enhancers (ESEs). We previously derived position weight matrices to predict putative ESEs specific for four human SR proteins. The score matrices are part of ESEfinder, an online resource to identify ESEs in query sequences. We have now carried out a refined functional SELEX screen for motifs that can act as ESEs in response to the human SR protein SF2/ASF. The test BRCA1 exon under selection was internal, rather than the 3'-terminal IGHM exon used in our earlier studies. A naturally occurring heptameric ESE in BRCA1 exon 18 was replaced with two libraries of random sequences, one seven nucleotides in length, the other 14. Following three rounds of selection for in vitro splicing via internal exon inclusion, new consensus motifs and score matrices were derived. Many winner sequences were demonstrated to be functional ESEs in S100-extract-complementation assays with recombinant SF2/ASF. Motif-score threshold values were derived from both experimental and statistical analyses. Motif scores were shown to correlate with levels of exon inclusion, both in vitro and in vivo. Our results confirm and extend our earlier data, as many of the same motifs are recognized as ESEs by both the original and our new score matrix, despite the different context used for selection. Finally, we have derived an increased specificity score matrix that incorporates information from both of our SF2/ASF-specific matrices and that accurately predicts the exon-skipping phenotypes of deleterious point mutations.

Alternative Splicing↗

PubMed2006

Molecular genetic studies of the memory of winter.

Many plant species have evolved the ability to flower in the proper season by sensing environmental cues. The prolonged cold of winter is one such cue that certain plants use to acquire competence to flower the following spring. For example, biennials and winter annuals become established in one growing season and often flower quickly in the early spring of the following year to complete their life cycles. The process by which exposure to prolonged cold establishes competence to flower is known as vernalization. Many studies, starting with the classic work of Lang and Melchers, have shown that the vernalized state can be stable; i.e. after exposure to cold has ended, competence to flower, in certain species, can persist for many months and throughout many cell divisions in the shoot apical meristem. Thus, plants can exhibit a 'memory of winter' and vernalization can result in an epigenetic switch in the classic sense of the term: a change that is stable in the absence of the inducing signal. The nature of this epigenetic switch in Arabidopsis thaliana is discussed here.

Amino Acid Sequence↗

PubMed2006

Genomic inferences of the cis-regulatory nucleotide polymorphisms underlying gene expression differences between Drosophila melanogaster mating races.

Nucleotide sequence polymorphisms affecting gene expression occur in the regulatory region of genes (in cis) and elsewhere in the genome (in trans). Further study is required to weigh the relative importance of cis- and trans-acting mutations in mediating gene expression differences within and between species. Here, microarray hybridization experiments were used to isolate 363 gene expression differences between the female fly head transcriptomes of 2 Drosophila melanogaster strains. One strain (French) represented the cosmopolitan M mating race and the other strain (ZS30) represented the Z mating race derived from Zimbabwe, Africa. From chromosomal substitution strains engineered from the 2 strains, we inferred that the expression differences between M and Z alleles largely could be attributed to the genotype of the chromosomes where the differentially expressed genes were located, that is, cis-regulatory polymorphisms prominently influence gene expression differences between M and Z. The effects of trans-regulatory polymorphisms were apparent yet difficult to quantify. Results have implications for models of gene regulatory evolution as well as experimental studies trying to identify the nucleotide sequence polymorphisms underlying gene expression differences between Drosophila strains.

Animals↗

PubMed1993

Regulatory elements necessary for termination of transcription within the Ig heavy chain gene locus.

Previous experiments have shown that the extent of delta gene transcription during B cell development is regulated primarily at the transcriptional level. We have shown that deletion of a sequence located between the mu and delta coding regions in the Ig heavy chain locus where transcriptional termination has been previously mapped abrogates the termination. Restoration of termination requires reintroduction of this segment as well as sequence elements within the microM poly (A) site which cannot be substituted by the microS poly (A) site. Recognition of the termination site by non-lymphoid cells suggests that initiation of delta transcription in mature B lymphocytes requires the activation of an anti-termination mechanism not yet developed in early B cells.

Animals↗

PubMed2006

MicroFootPrinter: a tool for phylogenetic footprinting in prokaryotic genomes.

Phylogenetic footprinting is a method for the discovery of regulatory elements in a set of homologous regulatory regions, usually collected from multiple species. It does so by identifying the most conserved motifs in those homologous regions. This note describes web software that has been designed specifically for this purpose in prokaryotic genomes, making use of the phylogenetic relationships among the homologous sequences in order to make more accurate predictions. The software is called MicroFootPrinter and is available at http://bio.cs.washington.edu/software.html.

Genome, Archaeal↗

PubMed2006

iCR: a web tool to identify conserved targets of a regulatory protein across the multiple related prokaryotic species.

Gene regulatory circuits are often commonly shared between two closely related organisms. Our web tool iCR (identify Conserved target of a Regulon) makes use of this fact and identify conserved targets of a regulatory protein. iCR is a special refined extension of our previous tool PredictRegulon- that predicts genome wide, the potential binding sites and target operons of a regulatory protein in a single user selected genome. Like PredictRegulon, the iCR accepts known binding sites of a regulatory protein as ungapped multiple sequence alignment and provides the potential binding sites. However important differences are that the user can select more than one genome at a time and the output reports the genes that are common in two or more species. In order to achieve this, iCR makes use of Cluster of Orthologous Group (COG) indices for the genes. This tool analyses the upstream region of all user-selected prokaryote genome and gives the output based on conservation target orthologs. iCR also reports the Functional class codes based on COG classification for the encoded proteins of downstream genes which helps user understand the nature of the co-regulated genes at the result page itself. iCR is freely accessible at http://www.cdfd.org.in/icr/.

Bacterial Proteins↗

PubMed2006

jPREdictor: a versatile tool for the prediction of cis-regulatory elements.

Gene regulation is the process through which an organism effects spatial and temporal differences in gene expression levels. Knowledge of cis-regulatory elements as key players in gene regulation is indispensable for the understanding of the latter and of the development of organisms. Here we present the tool jPREdictor for the fast and versatile prediction of cis-regulatory elements on a genome-wide scale. The prediction is based on clusters of individual motifs and any combination of these into multi-motifs with selectable minimal and maximal distances. Individual motifs can be of heterogenous classes, such as simple sequence motifs or position-specific scoring matrices. Cluster scores are weighted occurrences of multi-motifs, where the weights are derived from positive and negative training sets. We illustrate the flexibility of the jPREdictor with a new predic-tion of Polycomb/Trithorax Response Elements in Drosophila melanogaster. jPREdictor is available as a graphical user interface for online use and for download at http://bibiserv.techfak.uni-bielefeld.de/jpredictor.

Animals↗

PubMed2006

SwissRegulon: a database of genome-wide annotations of regulatory sites.

SwissRegulon (http://www.swissregulon.unibas.ch) is a database containing genome-wide annotations of regulatory sites in the intergenic regions of genomes. The regulatory site annotations are produced using a number of recently developed algorithms that operate on multiple alignments of orthologous intergenic regions from related genomes in combination with, whenever available, known sites from the literature, and ChIP-on-chip binding data. Currently SwissRegulon contains annotations for yeast and 17 prokaryotic genomes. The database provides information about the sequence, location, orientation, posterior probability and, whenever available, binding factor of each annotated site. To enable easy viewing of the regulatory site annotations in the context of other features annotated on the genomes, the sites are displayed using the GBrowse genome browser interface and can be queried based on any annotated genomic feature. The database can also be queried for regulons, i.e. sites bound by a common factor.

Algorithms↗

PubMed1989

Tissue-specific DNA binding of nuclear proteins that bind to the adenovirus inverted terminal repeat.

Adenovirus (Ad) DNA replication requires nuclear factor I (NFI), a cellular sequence-specific DNA binding protein which binds to the Ad DNA inverted terminal repeat (ITR). The NFI binding consensus sequence, TGGN6-7GCCAA, possibly includes the CCAAT-box which is often observed in regulatory elements of transcription. Adjacent to the NFI binding site on the Ad ITR is the binding site for nuclear factor III (NFIII), another cellular factor that stimulates Ad DNA replication in a cell-free system. Using gel retardation assay, we have examined the tissue specificity of these DNA binding activities in mouse. High NFI activity was detected in nuclear extracts from mouse liver, kidney, and spleen. Competition gel retardation assay with double-stranded oligonucleotides containing herpes simplex virus thymidine kinase (HSV-TK) gene or hsp70 gene CCAAT-box showed no effect on mouse NFI binding to its binding site. In the course of competitive DNA-binding assay, we detected a novel DNA binding protein in mouse kidney nuclear extracts, designated nuclear factor K (NFK). The NFK binding site is included in the NFIII binding site on the Ad ITR. NFK seems to be different from NFIII, in mode of binding to its binding site.

Adenoviridae↗

PubMed1993

Cloning and characterization of a tryptophanase gene from Enterobacter aerogenes SM-18.

A tryptophanase gene from Enterobacter aerogenes SM-18 was cloned and sequenced. The structural gene for tryptophanase, tnaA, consisted of 1389 bp encoding 462 amino acid residues, and its nucleotide sequence and deduced amino acid sequence showed significant homology to those of tnaA from Escherichia coli K12. A short open reading frame consisting of 31 amino acid residues was found upstream of tnaA, and it showed some similarity to the E. coli tnaC gene known to be a cis-acting regulatory element for transcription. A partial open reading frame homologous to the 5' end of E. coli tnaB was observed at the 3'-flanking region of tnaA. These genes may thus constitute an operon as in E. coli.

Amino Acid Sequence↗

PubMed2007

The RNA2 5' leader of Blackcurrant reversion virus mediates efficient in vivo translation through an internal ribosomal entry site mechanism.

The 5' and 3' non-translated regions (NTRs) of mRNAs of eukaryotes and their viruses often contain translational enhancers, including internal ribosomal entry sites (IRESs) comprised in the 5' leaders of many uncapped viral mRNAs. Blackcurrant reversion virus (BRV) has a genome composed of two uncapped, polyadenylated RNAs with relatively short 5' NTRs, almost devoid of secondary structure. In this work, a role of the RNA2 5' NTR in translation was studied by using mono- and dicistronic Photinus pyralis and Renilla reniformis luciferase reporter mRNAs in protoplasts of Nicotiana benthamiana. The RNA2 5' leader was found to confer efficient in vivo translation compared with the control 5' NTR, and each half of the BRV leader was essential for stimulatory function. Such efficient translational enhancement was mediated, at least in part, through an IRES mechanism. Multiple RNA2 5' NTR regions, complementary to a fragment of plant 18S rRNA demonstrated previously to be accessible for intermolecular mRNA-rRNA interactions and conserved between eukaryotes, were shown to be important for efficient translation. Similar mRNA-rRNA base-pairing potential was also predicted for the 5' leaders of other nepoviruses.

3' Untranslated Regions↗

PubMed2005

Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS).

A major goal in genomics is to understand how genes are regulated in different tissues, stages of development, diseases, and species. Mapping DNase I hypersensitive (HS) sites within nuclear chromatin is a powerful and well-established method of identifying many different types of regulatory elements, but in the past it has been limited to analysis of single loci. We have recently described a protocol to generate a genome-wide library of DNase HS sites. Here, we report high-throughput analysis, using massively parallel signature sequencing (MPSS), of 230,000 tags from a DNase library generated from quiescent human CD4+ T cells. Of the tags that uniquely map to the genome, we identified 14,190 clusters of sequences that group within close proximity to each other. By using a real-time PCR strategy, we determined that the majority of these clusters represent valid DNase HS sites. Approximately 80% of these DNase HS sites uniquely map within one or more annotated regions of the genome believed to contain regulatory elements, including regions 2 kb upstream of genes, CpG islands, and highly conserved sequences. Most DNase HS sites identified in CD4+ T cells are also HS in CD8+ T cells, B cells, hepatocytes, human umbilical vein endothelial cells (HUVECs), and HeLa cells. However, approximately 10% of the DNase HS sites are lymphocyte specific, indicating that this procedure can identify gene regulatory elements that control cell type specificity. This strategy, which can be applied to any cell line or tissue, will enable a better understanding of how chromatin structure dictates cell function and fate.

Cell Differentiation↗