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PubMed2005

Identification of novel steroid target genes through the combination of bioinformatics and functional analysis of hormone response elements.

Steroid hormone receptors including androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), and mineralocorticoid receptor (MR) recognize and bind to identical consensus hormone response elements (HREs), which consist of two hexameric half-sites (5'-AGAACA-3') arranged as inverted repeats with a 3-bp spacer. Although only a few near-consensus HRE sequences have been identified in the transcriptional regulatory regions of known steroid target genes, it has been unclear whether the exact consensus sequences function as bona fide HREs in vivo. A genome-wide in silico screening of palindromic HREs identified 565 exact consensus sequences in human genome (NCBI 35 assembly). In this study, of 565 exact consensus elements, functional in vivo receptor binding was evaluated regarding 26 sequences located within 10 kb upstream to the 5' end of annotated genes through chromatin immunoprecipitation (ChIP) assay using cells endogenously expressing steroid hormone receptors. Hormone responsiveness of proximal gene expression was examined through quantitative RT-PCR. As far as performing ChIP assay for AR, GR, and PR, 14 of 26 elements significantly recruited at least one of the receptors by hormone treatment (>2-fold enrichment versus vehicle). In terms of gene expression in the vicinity of the above 14 functional perfect HREs, four genes were upregulated by >2-fold with hormone treatment. The present data suggest that the combination of bioinformatics analysis and quantitative experimental evaluation is useful to identify novel functional HREs that may contribute to the transcriptional regulation of steroid target genes.

Cell Line, Tumor↗

PubMed2002

Characterizing the metabolic phenotype: a phenotype phase plane analysis.

Genome-scale metabolic maps can be reconstructed from annotated genome sequence data, biochemical literature, bioinformatic analysis, and strain-specific information. Flux-balance analysis has been useful for qualitative and quantitative analysis of metabolic reconstructions. In the past, FBA has typically been performed in one growth condition at a time, thus giving a limited view of the metabolic capabilities of a metabolic network. We have broadened the use of FBA to map the optimal metabolic flux distribution onto a single plane, which is defined by the availability of two key substrates. A finite number of qualitatively distinct patterns of metabolic pathway utilization were identified in this plane, dividing it into discrete phases. The characteristics of these distinct phases are interpreted using ratios of shadow prices in the form of isoclines. The isoclines can be used to classify the state of the metabolic network. This methodology gives rise to a "phase plane" analysis of the metabolic genotype-phenotype relation relevant for a range of growth conditions. Phenotype phase planes (PhPPs) were generated for Escherichia coli growth on two carbon sources (acetate and glucose) at all levels of oxygenation, and the resulting optimal metabolic phenotypes were studied. Supplementary information can be downloaded from our website (http://epicurus.che.udel.edu).

Computational Biology↗

PubMed2005

GNARE: automated system for high-throughput genome analysis with grid computational backend.

Recent progress in genomics and experimental biology has brought exponential growth of the biological information available for computational analysis in public genomics databases. However, applying the potentially enormous scientific value of this information to the understanding of biological systems requires computing and data storage technology of an unprecedented scale. The Grid, with its aggregated and distributed computational and storage infrastructure, offers an ideal platform for high-throughput bioinformatics analysis. To leverage this we have developed the Genome Analysis Research Environment (GNARE)--a scalable computational system for the high-throughput analysis of genomes, which provides an integrated database and computational backend for data-driven bioinformatics applications. GNARE efficiently automates the major steps of genome analysis including acquisition of data from multiple genomic databases; data analysis by a diverse set of bioinformatics tools; and storage of results and annotations. High-throughput computations in GNARE are performed using distributed heterogeneous Grid computing resources such as Grid2003, TeraGrid, and the DOE Science Grid. Multi-step genome analysis workflows involving massive data processing, the use of application-specific tools and algorithms and updating of an integrated database to provide interactive web access to results are all expressed and controlled by a "virtual data" model which transparently maps computational workflows to distributed Grid resources. This paper describes how Grid technologies such as Globus, Condor, and the Gryphyn Virtual Data System were applied in the development of GNARE. It focuses on our approach to Grid resource allocation and to the use of GNARE as a computational framework for the development of bioinformatics applications.

Computational Biology↗

PubMed2026

Thyroid hormone deprivation creates an immunological signature in the mouse liver, involving Kupffer cell presentation as the mouse ages.

PURPOSE: Aging is associated with an increased prevalence of chronic liver diseases suggesting impaired immune and metabolic function. In addition, thyroid hormone (TH) impacts liver physiology and TH deprivation or excess negatively affect organ maintenance. However, whether age-dependent consequences of TH alterations are reflected in a liver-specific adaptation is unknown so far. The present study aimed to characterize the impact of TH deprivation or excess on the liver transcriptome during aging. METHODS: Five- and 21-month-old male C57BL/6 mice were exposed either to chronic TH deprivation or to chronic TH excess and compared to control treatment by microarray-based liver transcriptome analysis. RESULTS: Significant roles of both TH state and age became obvious: Bioinformatic analysis of the liver transcriptome data revealed an age-dependent immune signature by chronic TH deprivation, an age-dependent immune and metabolic signature independent of exogenous TH modulation, as well as an age-dependent metabolic signature by chronic TH excess. Published data of single cell transcriptomic atlas characterizing aging tissues in the mouse were compared with our data and revealed Kupffer cell presentation in the immunological signature by TH deprivation during aging. Literature data for four prominent differentially expressed genes, namely C1qb, C3ar1, Ctss, and Msr1, revealed that the complement system, extracellular matrix remodelling, as well as the proinflammatory phenotype of Kupffer cells are altered by TH deprivation during aging. CONCLUSION: In conclusion, our study illuminates the interplay between TH deprivation, aging, and liver transcriptome signatures, highlighting potential implications for immune function and tissue maintenance, particularly through the modulation of Kupffer cell presentation.

Animals↗

PubMed2006

Analysis of circular genome rearrangement by fusions, fissions and block-interchanges.

BACKGROUND: Analysis of genomes evolving via block-interchange events leads to a combinatorial problem of sorting by block-interchanges, which has been studied recently to evaluate the evolutionary relationship in distance between two biological species since block-interchange can be considered as a generalization of transposition. However, for genomes consisting of multiple chromosomes, their evolutionary history should also include events of chromosome fusions and fissions, where fusion merges two chromosomes into one and fission splits a chromosome into two. RESULTS: In this paper, we study the problem of genome rearrangement between two genomes of circular and multiple chromosomes by considering fusion, fission and block-interchange events altogether. By use of permutation groups in algebra, we propose an O (n2) time algorithm to efficiently compute and obtain a minimum series of fusions, fissions and block-interchanges required to transform one circular multi-chromosomal genome into another, where n is the number of genes shared by the two studied genomes. In addition, we have implemented this algorithm as a web server, called FFBI, and have also applied it to analyzing by gene orders the whole genomes of three human Vibrio pathogens, each with multiple and circular chromosomes, to infer their evolutionary relationships. Consequently, our experimental results coincide well with our previous results obtained using the chromosome-by-chromosome comparisons by landmark orders between any two Vibrio chromosomal sequences as well as using the traditional comparative analysis of 16S rRNA sequences. ConclusionFFBI is a useful tool for the bioinformatics analysis of circular and multiple genome rearrangement by fusions, fissions and block-interchanges.

Algorithms↗

PubMed2003

Computational tools for the study of allergens.

Allergy is a major cause of morbidity worldwide. The number of characterized allergens and related information is increasing rapidly creating demands for advanced information storage, retrieval and analysis. Bioinformatics provides useful tools for analysing allergens and these are complementary to traditional laboratory techniques for the study of allergens. Specific applications include structural analysis of allergens, identification of B- and T-cell epitopes, assessment of allergenicity and cross-reactivity, and genome analysis. In this paper, the most important bioinformatic tools and methods with relevance to the study of allergy have been reviewed.

Allergens↗

PubMed2000

Bioinformatics in protein analysis.

The chapter gives an overview of bioinformatic techniques of importance in protein analysis. These include database searches, sequence comparisons and structural predictions. Links to useful World Wide Web (WWW) pages are given in relation to each topic. Databases with biological information are reviewed with emphasis on databases for nucleotide sequences (EMBL, GenBank, DDBJ), genomes, amino acid sequences (Swissprot, PIR, TrEMBL, GenePept), and three-dimensional structures (PDB). Integrated user interfaces for databases (SRS and Entrez) are described. An introduction to databases of sequence patterns and protein families is also given (Prosite, Pfam, Blocks). Furthermore, the chapter describes the widespread methods for sequence comparisons, FASTA and BLAST, and the corresponding WWW services. The techniques involving multiple sequence alignments are also reviewed: alignment creation with the Clustal programs, phylogenetic tree calculation with the Clustal or Phylip packages and tree display using Drawtree, njplot or phylo_win. Finally, the chapter also treats the issue of structural prediction. Different methods for secondary structure predictions are described (Chou-Fasman, Garnier-Osguthorpe-Robson, Predator, PHD). Techniques for predicting membrane proteins, antigenic sites and postranslational modifications are also reviewed.

Computational Biology↗

PubMed2006

Identification of Alu elements mediating a partial PMP22 deletion.

Hereditary neuropathy with liability to pressure palsies (HNPP) is most frequently caused by deletion of a 1.4-Mb region in chromosome 17p11.2-12 including the peripheral myelin protein 22 (PMP22) gene. Smaller deletions partially affecting the PMP22 gene are less frequently observed. We identified in a HNPP patient a deletion of the 5' region of PMP22 including non-coding exon 1, coding exons 2 and 3, whereas, exons 4 and 5 were present. PMP22 exon 3- and 4-specific qPCR resulted in a deletion of one exon 3 allele but in the presence of 2 exon 4 alleles. SNP analysis revealed the presence of heterozygosity for PMP22 coding exons 4 and 5. Finally, MLPA specific for the CMT1A region defined this deletion for the entire 5' region of PMP22 (exons 1, 2 and 3). These partial HNPP deletions may be missed by other techniques, e.g., STR marker analysis. Alu elements have been reported to mediate non-allelic recombination events. Bioinformatic analysis revealed 12 Alu elements flanking in close neighbourhood the estimated 40-kb deletion region as candidates for recombination events. PCR primers were designed to identify a breakpoint-spanning product including the respective Alu elements. PCR-driven identification of a junction fragment was successful with AluJo-AluSq and AluYb9-AluSq specific primer pairs comprising the same intronic region of PMP22. Sequence analysis of these breakpoint-overlapping PCR fragments revealed a 29-bp motif including a chi-like sequence (GCTGG) present both in the AluYb9 and the AluSq element. These data confirm that low-copy repeats (LCRs) mediate non-allelic homologous recombinations (NAHR).

Alu Elements↗

PubMed2005

Unexpected identification of two interstitial deletions in a patient with a pericentric inversion of a chromosome 4 and an abnormal phenotype.

Interstitial deletions and pericentric inversions of chromosome 4 appear to be unusual phenomena. Here, we report the case of a 14-year-old boy with severe psychomotor retardation with a de novo 46,XY,der(4)del(p15.2p15.31)inv(4)(p15.2q13.3)del(4)(q13.2q13.2) karyotype. We used FISH analysis with YAC and BAC clones to characterise the inversion's breakpoints. A complex event with six breakpoints was found, characterised by a pericentric inversion and two deletions, the first on the short arm of chromosome 4 (4p) and the second on the long arm of chromosome 4 (4q). The deletion events had removed two segments, one of approximately 5 Mb, from 4p, outside the inversion, and the other 2 Mb from 4q, inside the inversion. These rearrangements were not found in the parents. Microsatellite marker analysis showed that the inversion carrying chromosome 4 was derived from the father. Bioinformatic analysis of the human genome sequence allowed us to identify several hemizygotic genes in the patient, which might be involved in the pathogenesis of this clinical phenotype.

Abnormalities, Multiple↗

PubMed2005

Analysis of DNA-protein interactions in complexes of transcription factor NF-kappaB with DNA.

We have applied bioinformatic analysis of X-ray 3D structures of complexes of transcription factor NF-kappaB with DNAs. We determined the number of possible Van der Waals contacts and hydrogen bonds between amino acid residues and nucleotides. Conservative contacts in the NF-kappaB dimer-DNA complex composed of p50 and/or p65 NF-kappaB subunit and DNA sequences like 5 -GGGAMWTTCC-3 were revealed. Based on these results, we propose a novel scheme for interactions between NF-kappaB p50 homodimer and the kappaB region of the immunoglobulin light chain gene enhancer (Ig-kappaB). We applied a chemical cross-linking technique to study the proximity of some Lys and Cys residues of NF-kappaB p50 subunit with certain reactive nucleotides into its recognition site. In all cases, the experimentally determined protein-DNA contacts were in good agreement with the predicted ones.

Amino Acid Sequence↗

PubMed2000

Analysis of the splicing machinery in fission yeast: a comparison with budding yeast and mammals.

Based on genetic and bioinformatic analysis, 80 proteins from the newly sequenced Schizosaccharomyces pombe genome appear to be splicing factors. The fission yeast splicing factors were compared to those of Homo sapiens and Saccharomyces cerevisiae in order to determine the extent of conservation or divergence that has occurred over the billion years of evolution that separate these organisms. Our results indicate that many of the factors present in all three organisms have been well conserved throughout evolution. It is calculated that 38% of the fission yeast splicing factors are more similar to the human proteins than to the budding yeast proteins (>10% more similar or similar over a greater region). Many of the factors in this category are required for recognition of the 3' splice site. Ten fission yeast splicing factors, including putative regulatory factors, have human homologs, but no apparent budding yeast homologs based on sequence data alone. Many of the budding yeast factors that are absent in fission yeast are associated with the U1 and U4/U6.U5 snRNP. Collectively the data presented in this survey indicate that of the two yeasts, S.POMBE: contains a splicing machinery more closely reflecting the archetype of a spliceosome.

Animals↗

PubMed2003

Cytomics in predictive medicine.

Patient-specific, disease-course predictions with >95% or >99% accuracy during therapy would be highly valuable for everyday medicine. If these predictors were available, disease aggravation or progression, frequently accompanied by irreversible tissue damage or therapeutic side effects, could then potentially be avoided by early preventive therapy. The molecular analysis of heterogeneous cellular systems (cytomics) by cytometry in conjunction with pattern-oriented bioinformatic analysis of the multiparametric cytometric and other data provides a promising approach to individualized or personalized medical treatment or disease management. As a consequence, better patient care and new forms of inductive scientific hypothesis development based on the interpretation of predictive data patterns are at reach.

Computational Biology↗

PubMed2004

Lipoproteins of Mycobacterium tuberculosis: an abundant and functionally diverse class of cell envelope components.

Mycobacterium tuberculosis remains the predominant bacterial scourge of mankind. Understanding of its biology and pathogenicity has been greatly advanced by the determination of whole genome sequences for this organism. Bacterial lipoproteins are a functionally diverse class of membrane-anchored proteins. The signal peptides of these proteins direct their export and post-translational lipid modification. These signal peptides are amenable to bioinformatic analysis, allowing the lipoproteins encoded in whole genomes to be catalogued. This review applies bioinformatic methods to the identification and functional characterisation of the lipoproteins encoded in the M. tuberculosis genomes. Ninety nine putative lipoproteins were identified and so this family of proteins represents ca. 2.5% of the M. tuberculosis predicted proteome. Thus, lipoproteins represent an important class of cell envelope proteins that may contribute to the virulence of this major pathogen.

Bacterial Proteins↗

PubMed2003

Salusins: newly identified bioactive peptides with hemodynamic and mitogenic activities.

The discovery of endogenous bioactive peptides has typically required a lengthy identification process. Computer-assisted analysis of cDNA and genomic DNA sequence information can markedly shorten the process. A bioinformatic analysis of full-length, enriched human cDNA libraries searching for previously unidentified bioactive peptides resulted in the identification and characterization of two related peptides of 28 and 20 amino acids, which we designated salusin-alpha and salusin-beta. Salusins are translated from an alternatively spliced mRNA of TOR2A, a gene encoding a protein of the torsion dystonia family. Intravenous administration of salusin-alpha or salusin-beta to rats causes rapid, profound hypotension and bradycardia. Salusins increase intracellular Ca2+, upregulate a variety of genes and induce cell mitogenesis. Salusin-beta stimulates the release of arginine-vasopressin from rat pituitary. Expression of TOR2A mRNA and its splicing into preprosalusin are ubiquitous, and immunoreactive salusin-alpha and salusin-beta are detected in many human tissues, plasma and urine, suggesting that salusins are endocrine and/or paracrine factors.

Adenosine Triphosphatases↗

PubMed2006

Functional study of a novel single deletion in the TITF1/NKX2.1 homeobox gene that produces congenital hypothyroidism and benign chorea but not pulmonary distress.

CONTEXT: We studied two sisters with congenital hypothyroidism and choreoathetosis but not respiratory distress. OBJECTIVE: The aim of this study was to establish the genetic defect that causes this phenotype and study the molecular mechanisms of the pathology by means of functional analysis. DESIGN: Sequencing of DNA, expression vectors generation, EMSAs, transfections experiments as well as bioinformatics analysis were performed. RESULTS: We found a new single deletion (825delC) in one allele of the TITF1/NKX2.1 gene. The mutation located in the C-terminal domain generates a nonsense thyroid transcription factor 1 (TTF1) protein, with 22 amino less and rich in positive charges. This protein shows diminished binding to DNA, does not interfere with wild-type (wt) TTF1 binding, and fails to activate reporter genes harboring the thyroglobulin (Tg), thyroperoxidase (TPO), or surfactant protein B (SP-B) promoters. In addition, the mutant (mut) protein has a dominant-negative effect on the transcriptional activity of wt TTF1 in a promoter-specific manner, inhibiting the transcription of Tg and TPO but not of SP-B. Using a Gal4 reporter system, we demonstrate that the mut protein is not transcriptionally active and does not likely compete with the wild type for coactivators. Interestingly, the mut protein impairs the wt capacity to synergize with paired box 8 (PAX8). This cooperation is necessary for Tg and TPO transcription but dispensable for SP-B expression. CONCLUSION: These results are concordant with the phenotype of the two sisters studied and demonstrate a differential role for TTF1 in the different tissues in which it is expressed.

Amino Acid Sequence↗

PubMed2025

Effect of Chang'an decoction on ulcerative colitis by regulating T helper 17 cells and regulatory T cellsRab27 in the p53/high mobility group box 1 pathway.

OBJECTIVE: To explore the effect of Chang'an decoction (, CAD) of ameliorating the immune imbalances in ulcerative colitis (UC) by regulating Rab27 in the P53/high mobility group box 1 pathway. METHODS: The functions and important signaling pathways of the Rab27- and UC-related genes were analyzed viathe use of microarray data from the gene expression omnibus database, gene ontology database, Kyoto encyclopedia of genes and genomes database and gene set enrichment analysis. Dextran sulfate sodium salt-induced colitis mouse model was used to verify the bioinformatics results. Colon length, body weight, and disease activity index were measured. Hematoxylin and eosin staining was applied to validate the histopathology. Tight junction proteins were detected by immunohistochemistry. The proportions of T helper 17 cells (Th17) and regulatory T cells (Treg) in mesenteric lymph nodes were measured viaflow cytometry. Proinflammatory cytokines like interleukin (IL) 17 (IL-17), IL-21 and IL-22 and anti-inflammatory cytokines like transforming growth factor β and IL-10 in the serum and colon of mice were detected by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction, respectively. The expression levels of high mobility group box 1 (HMGB1), P53 and phospho- P53 (P-P53) in colonic tissues were detected by immunofluorescence and Western blotting. RESULTS: Bioinformatics analysis revealed that compared with normal tissues, the expression of Rab27 was significantly increased in UC tissues. Receiver operating characteristic curve showed that Rab27 has the potential to be used as a biomarker for the diagnosis of disease activity. Enrichment analysis showed that UC and Rab27 were mainly associated with small molecule transport, nutrient metabolism, transmembrane transport and the downstream pathway of P53. According to animal experiments, the expression of Rab27 was increased in UC tissues, which aggravated the colonic pathological damage, activated the expression of HMGB1, and also leaded to the imbalance of Th17 and Treg cells. After CAD intervention, Rab27 overexpression, weight loss, colon shortening, and pathological damage were substantial reduced, the expression of tight junction proteins, zona occludens 1 and Occludin were increased. The effect of CAD at high-dose was more obvious. In addition, CAD upgraded the number of Treg cells and the production of TGF-β and IL-10, while decreasing the number of Th17 cells and the expression of inflammatory cytokines (IL-17, IL-21, and IL-22). Moreover, colon inflammation was alleviated by CAD, as indicated by the regulation of HMGB1 and P-P53 expression. CONCLUSION: The expression of Rab27, HMGB1 and P-P53 could be decreased by CAD, and the balance of Th17 and Treg cells as well as their related cytokines could be regulated by CAD.

Animals↗

PubMed2006

Characterization of a megakaryocyte-specific enhancer of the key hemopoietic transcription factor GATA1.

Specification and differentiation of the megakaryocyte and erythroid lineages from a common bipotential progenitor provides a well studied model to dissect binary cell fate decisions. To understand how the distinct megakaryocyte- and erythroid-specific gene programs arise, we have examined the transcriptional regulation of the megakaryocyte erythroid transcription factor GATA1. Hemopoietic-specific mouse (m)GATA1 expression requires the mGata1 enhancer mHS-3.5. Within mHS-3.5, the 3' 179 bp of mHS-3.5 are required for megakaryocyte but not red cell expression. Here, we show mHS-3.5 binds key hemopoietic transcription factors in vivo and is required to maintain histone acetylation at the mGata1 locus in primary megakaryocytes. Analysis of GATA1-LacZ reporter gene expression in transgenic mice shows that a 25-bp element within the 3'-179 bp in mHS-3.5 is critical for megakaryocyte expression. In vitro three DNA binding activities A, B, and C bind to the core of the 25-bp element, and these binding sites are conserved through evolution. Activity A is the zinc finger transcription factor ZBP89 that also binds to other cis elements in the mGata1 locus. Activity B is of particular interest as it is present in primary megakaryocytes but not red cells. Furthermore, mutation analysis in transgenic mice reveals activity B is required for megakaryocyte-specific enhancer function. Bioinformatic analysis shows sequence corresponding to the binding site for activity B is a previously unrecognized motif, present in the cis elements of the Fli1 gene, another important megakaryocyte-specific transcription factor. In summary, we have identified a motif and a DNA binding activity likely to be important in directing a megakaryocyte gene expression program that is distinct from that in red cells.

Animals↗

PubMed2005

What's in a character?

Systematic analyses are included as integral parts of bioinformatic analysis. The use of phenetic and phylogenetic trees in many of the newer areas of biology create a need for bioinformaticists to understand more completely the nuances of systematic analysis. Any description in comparative biology, universally begins with what information to use in the comparative endeavor. Phylogenetic approaches are no different. The diversity of approaches and phylogenetic questions in systematics have sometimes hindered a precise understanding of what primary data should be collected to perform such analyses. In addition, one should always keep in mind that the objective of systematic organization of entities in nature not only strives to organize those entities in an objective, repeatable and operational way, but also to organize the attributes of the entities in a similar hierarchical context. This paper attempts to describe characters as the basis of all comparative analysis, to describe the diverse kinds of primary data that exist today in biology, genomics, and bioinformatics, and to place these kinds of primary data in the context of the established approaches to tree building.

Animals↗