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PubMed2026

Deciphering the genetic background of an industrial 2-ketogluconic acid-producing strain Pseudomonas plecoglossicida JUIM01 using whole-genome sequencing.

2-Ketogluconic acid (2KGA) is an important precursor for the food antioxidant erythorbic acid, currently produced via microbial fermentation using Pseudomonas species. To facilitate the genetic improvement of production strains, the complete genome of an industrial 2KGA producer P. plecoglossicida JUIM01 was sequenced and analyzed. The genome consists of a 5.13-Mb circular chromosome with a GC content of 63.58%, encoding 4,517 predicted proteins. Comprehensive functional annotation identified a putative global regulatory network comprising 75 core regulators, which were classified into six functionally cooperative modules, potentially governing the strain's metabolism and environmental adaptability. We further delineated the genetic determinants hypothetically linked to efficient 2KGA synthesis, including glucose metabolism, fatty acid metabolism, and the oxidative phosphorylation system. These outputs could provide the genomic resource for elucidating high productivity and robustness, and rationally engineering the high-performance chassis cells toward robust 2KGA production.

P. plecoglossicida↗
PubMed2004

PLET1 (C11orf34), a highly expressed and processed novel gene in pig and mouse placenta, is transcribed but poorly spliced in human.

Sequencing of porcine cDNAs identified a novel EST with high frequency in placenta tissue. Full-length PLET1 (placenta-expressed transcript 1, also called C11orf34) matched a mouse cDNA and many bovine and mouse ESTs but no human transcripts or ESTs. However, the porcine cDNA matched several putative exons within a human genomic DNA fragment on chromosome 11. This human locus is in a region of conserved synteny with pig chromosome 9, to which the porcine gene was subsequently mapped. RNA blot hybridization showed that this gene had high expression in porcine and mouse conceptus and throughout placenta development. In situ hybridization using mouse placenta showed PLET1 expression in trophoblast cells of the labyrinth, as well as in spongiotrophoblast and glycogen trophoblast cells. However, no expression of PLET1 was detected by RNA blot analysis of human placenta, although RT-PCR analysis detected very small amounts of partially spliced RNA that were significantly less abundant than the RNA levels in mouse placenta. Donor and acceptor splicing site sequences in the exons of the human gene are poorly conserved and may be the cause of inefficient splicing found specifically in human tissue. Our data correct GenomeScan annotation of this region of the human genome and describe functional gene discovery in mammals not recognized in human EST projects.

Amino Acid Sequence↗
PubMed2002

Gene networks: how to put the function in genomics.

An increasingly popular model of regulation is to represent networks of genes as if they directly affect each other. Although such gene networks are phenomenological because they do not explicitly represent the proteins and metabolites that mediate cell interactions, they are a logical way of describing phenomena observed with transcription profiling, such as those that occur with popular microarray technology. The ability to create gene networks from experimental data and use them to reason about their dynamics and design principles will increase our understanding of cellular function. We propose that gene networks are also a good way to describe function unequivocally, and that they could be used for genome functional annotation. Here, we review some of the concepts and methods associated with gene networks, with emphasis on their construction based on experimental data.

Animals↗
PubMed2002

Structural diversity and transcription of class III peroxidases from Arabidopsis thaliana.

Understanding peroxidase function in plants is complicated by the lack of substrate specificity, the high number of genes, their diversity in structure and our limited knowledge of peroxidase gene transcription and translation. In the present study we sequenced expressed sequence tags (ESTs) encoding novel heme-containing class III peroxidases from Arabidopsis thaliana and annotated 73 full-length genes identified in the genome. In total, transcripts of 58 of these genes have now been observed. The expression of individual peroxidase genes was assessed in organ-specific EST libraries and compared to the expression of 33 peroxidase genes which we analyzed in whole plants 3, 6, 15, 35 and 59 days after sowing. Expression was assessed in root, rosette leaf, stem, cauline leaf, flower bud and cell culture tissues using the gene-specific and highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR). We predicted that 71 genes could yield stable proteins folded similarly to horseradish peroxidase (HRP). The putative mature peroxidases derived from these genes showed 28-94% amino acid sequence identity and were all targeted to the endoplasmic reticulum by N-terminal signal peptides. In 20 peroxidases these signal peptides were followed by various N-terminal extensions of unknown function which are not present in HRP. Ten peroxidases showed a C-terminal extension indicating vacuolar targeting. We found that the majority of peroxidase genes were expressed in root. In total, class III peroxidases accounted for an impressive 2.2% of root ESTs. Rather few peroxidases showed organ specificity. Most importantly, genes expressed constitutively in all organs and genes with a preference for root represented structurally diverse peroxidases (< 70% sequence identity). Furthermore, genes appearing in tandem showed distinct expression profiles. The alignment of 73 Arabidopsis peroxidase sequences provides an easy access to the identification of orthologous peroxidases in other plant species and will provide a common platform for combining knowledge of peroxidase structure and function relationships obtained in various species.

Amino Acid Sequence↗
PubMed2000

MultiFun, a multifunctional classification scheme for Escherichia coli K-12 gene products.

An enriched classification system for cellular functions of gene products of Escherichia coli K-12 was developed based on the initial classification by Riley. In the new classification scheme, MultiFun, cellular functions are divided into 10 major categories: Metabolism, Information Transfer, Regulation, Transport, Cell Processes, Cell Structure, Location, Extra-chromosomal Origin, DNA Site, and Cryptic Gene. These major categories are further sub-divided into a hierarchical scheme. Two thousand nine hundred twenty-two gene products of E. coli K-12 were assigned to one or more functions depending on the role they play in the cell. Functional assignments were made to 66% of E. coli gene products, ranging from 1 to 16 assignments per gene product. The expansion of cellular function categories and the assignment to more than one category (multifunction) provides a more complete description of the gene products and their roles and hence better reflects the functional complexity of organisms. We believe this classification system will be useful in the field of genome analysis, both for annotation purposes and for comparative studies. The functional classification scheme and the cellular function assignments made to E. coli gene products can be accessed from the web at the databases GenProtEC (http://genprotec.mbl.edu) and EcoCyc (http://www.ecocyc.org).

Bacterial Proteins↗
PubMed2005

Beyond the clause: extraction of phosphorylation information from medline abstracts.

MOTIVATION: Phosphorylation is an important biochemical reaction that plays a critical role in signal transduction pathways and cell-cycle processes. A text mining system to extract the phosphorylation relation from the literature is reported. The focus of this paper is on the new methods developed and implemented to connect and merge pieces of information about phosphorylation mentioned in different sentences in the text. The effectiveness and accuracy of the system as a whole as well as that of the methods for extraction beyond a clause/sentence is evaluated using an independently annotated dataset, the Phospho.ELM database. The new methods developed to merge pieces of information from different sentences are shown to be effective in significantly raising the recall without much difference in precision.

Artificial Intelligence↗
PubMed2003

Gene array analysis of bone morphogenetic protein type I receptor-induced osteoblast differentiation.

UNLABELLED: The genomic response to BMP was investigated by ectopic expression of activated BMP type I receptors in C2C12 myoblast using cDNA microarrays. Novel BMP receptor target genes with possible roles in inhibition of myoblast differentiation and stimulation of osteoblast differentiation were identified. INTRODUCTION: Bone morphogenetic proteins (BMPs) have an important role in controlling mesenchymal cell fate and mediate these effects by regulating gene expression. BMPs signal through three distinct specific BMP type I receptors (also termed activin receptor-like kinases) and their downstream nuclear effectors, termed Smads. The critical target genes by which activated BMP receptors mediate change cell fate are poorly characterized. MATERIALS AND METHODS: We performed transcriptional profiling of C2C12 myoblasts differentiation into osteoblast-like cells by ectopic expression of three distinct constitutively active (ca)BMP type I receptors using adenoviral gene transfer. Cells were harvested 48 h after infection, which allowed detection of both early and late response genes. Expression analysis was performed using the mouse GEM1 microarray, which is comprised of approximately 8700 unique sequences. Hybridizations were performed in duplicate with a reverse fluor labeling. Genes were considered to be significantly regulated if the p value for differential expression was less than 0.01 and inverted expression ratios per duplicate successful reciprocal hybridizations differed by less than 25%. RESULTS AND CONCLUSIONS: Each of the three caBMP type I receptors stimulated equal levels of R-Smad phosphorylation and alkaline phosphatase activity, an early marker for osteoblast differentiation. Interestingly, all three type I receptors induced identical transcriptional profiles; 97 genes were significantly upregulated and 103 genes were downregulated. Many extracellular matrix genes were upregulated, muscle-related genes downregulated, and transcription factors/signaling components modulated. In addition to 41 expressed sequence tags without known function and a number of known BMP target genes, including PPAR-gamma and fibromodulin, a large number of novel BMP target genes with an annotated function were identified, including transcription factors HesR1, ITF-2, and ICSBP, apoptosis mediators DRP-1 death kinase and ZIP kinase, IkappaB alpha, Edg-2, ZO-1, and E3 ligase Dactylin. These target genes, some of them unexpected, offer new insights into how BMPs elicit biological effects, in particular into the mechanism of inhibition of myoblast differentiation and stimulation of osteoblast differentiation.

Animals↗
PubMed2004

Molecular classification and molecular genetics of human lung cancers.

Recent advances in the molecular classification of lung carcinomas and the identification of causative genetic alterations will likely lead to improvements in the diagnosis and treatment of patients with lung cancer. It is now possible to identify gene expression profiles that associate with patient outcome in lung carcinomas, in particular adenocarcinoma. Furthermore, patient survival has been shown to correlate with lung cancer oligonucleotide microarray expression profiles. Large-scale microarray technology may allow for the identification of useful biomarkers for early cancer detection. Oligonucleotide microarray data can be optimized by relating them to protein expression levels in tissue microarrays, by annotation with mutational data, and with results of testing for post-translational modification of cellular proteins. These data may be useful in tailoring chemotherapeutic protocols to individual tumors and identifying new targets for therapeutic intervention.

Adenocarcinoma↗
PubMed1976

Ultrastructure of the human breast and its disorders.

The extant literature pertaining to the ultrastructural features of disorders of the human breast is reviewed and annotated with findings derived from a personal study of 82 patients whose specimens encompassed a wide variety of such lesions. In addition, observations of lesions heretofore undescribed are presented.

Adenocarcinoma, Mucinous↗
PubMed2004

Extensive analysis of the human platelet proteome by two-dimensional gel electrophoresis and mass spectrometry.

Platelets play a key role in the control of bleeding and wound healing, contributing to the formation of vascular plugs. Under pathologic circumstances, they are involved in thrombotic disorders, including heart disease. Since platelets do not have a nucleus, proteomics offers a powerful alternative approach to provide data on protein expression in these cells, helping to address their biology. In this publication we extend the previously reported analysis of the pI 4-5 region of the human platelet proteome to the pI 5-11 region. By using narrow pI range two-dimensional electrophoresis (2-DE) for protein separation followed by high-throughput tandem mass spectrometry (MS/MS) for protein identification, we were able to identify 760 protein features, corresponding to 311 different genes, resulting in the annotation of 54% of the pI 5-11 range 2-DE proteome map. We evaluated the physicochemical properties and functions of the identified platelet proteome. Importantly, the main group of proteins identified is involved in intracellular signalling and regulation of the cytoskeleton. In addition, 11 hypothetical proteins are reported. In conclusion, this study provides a unique inventory of the platelet proteome, contributing to our understanding of platelet function and building the basis for the identification of new drug targets.

Blood Platelets↗
PubMed2003

Computational methods and evaluation of RNA stabilization reagents for genome-wide expression studies.

Gene expression studies require high quality messenger RNA (mRNA) in addition to other factors such as efficient primers and labeling reagents. To prevent RNA degradation and to improve the quality of gene array expression data, several commercial reagents have become available. We examined a conventional hot-phenol lysis method and RNA stabilization reagents, and generated comparative gene expression profiles from Escherichia coli cells grown on minimal medium. Our data indicate that certain RNA stabilization reagents induce stress responses and proper caution must be exercised during their use. We observed that the laboratory reagent (phenol/EtOH, 5:95, v/v) worked efficiently in isolating high quality mRNA and reproducibility was such that reliable gene expression profiles were generated. To assist in the analysis of gene expression data, we wrote a number of macros that use the most recent gene annotation and process data in accordance with gene function. Scripts were also written to examine the occurrence of artifacts, based on GC content, length of the individual open reading frame (ORF), its distribution on plus and minus DNA strands, and the distance from the replication origin.

Base Composition↗
PubMed2004

Cloning, expression and identification of a new trehalose synthase gene from Thermobifida fusca genome.

A new open reading frame in Thermobifida fusca sequenced genome was identified to encode a new trehalose synthase, annotated as "glycosidase" in the GenBank database, by bioinformatics searching and experimental validation. The gene had a length of 1830 bp with about 65% GC content and encoded for a new trehalose synthase with 610 amino acids and deduced molecular weight of 66 kD. The high GC content seemed not to affect its good expression in E. coli BL21 in which the target protein could account for as high as 15% of the total cell proteins. The recombinant enzyme showed its optimal activities at 25 degrees and pH 6.5 when it converted substrate maltose into trehalose. However it would divert a high proportion of its substrate into glucose when the temperature was increased to 37 degrees, or when the enzyme concentration was high Its activity was not inhibited by 5 mM heavy metals such as Cu2+, Mn2+, and Zn2+ but affected by high concentration of glucose. Blasting against the database indicated that amino acid sequence of this protein had maximal 69% homology with the known trehalose synthases, and two highly conserved segments of the protein sequence were identified and their possible linkage with functions was discussed.

Actinomycetales↗
PubMed2002

The peptidyl-prolyl isomerase motif is lacking in PmpA, the PrsA-like protein involved in the secretion machinery of Lactococcus lactis.

The prsA-like gene from Lactococcus lactis encoding its single homologue to PrsA, an essential protein triggering the folding of secreted proteins in Bacillus subtilis, was characterized. This gene, annotated pmpA, encodes a lipoprotein of 309 residues whose expression is increased 7- to 10-fold when the source of nitrogen is limited. A slight increase in the expression of the PrsA-like protein (PLP) in L. lactis removed the degradation products previously observed with the Staphylococcus hyicus lipase used as a model secreted protein. This shows that PmpA either triggers the folding of the secreted lipase or activates its degradation by the cell surface protease HtrA. Unlike the case for B. subtilis, the inactivation of the gene encoding PmpA reduced only slightly the growth rate of L. lactis in standard conditions. However, it almost stopped its growth when the lipase was overexpressed in the presence of salt in the medium. Like PrsA of B. subtilis and PrtM of L. lactis, the L. lactis PmpA protein could thus have a foldase activity that facilitates protein secretion. These proteins belong to the third family of peptidyl-prolyl cis/trans-isomerases (PPIases) for which parvulin is the prototype. Almost all PLP from gram-positive bacteria contain a domain with the PPIase signature. An exception to this situation was found only in Streptococcaceae, the family to which L. lactis belongs. PLP from Streptococcus pneumoniae and Enterococcus faecalis possess this signature, but those of L. lactis, Streptococcus pyogenes, and Streptococcus mutans do not. However, secondary structure predictions suggest that the folding of PLP is conserved over the entire length of the proteins, including the unconserved signature region. The activity associated with the expression of PmpA in L. lactis and these genomic data show that either the PPIase motif is not necessary for PPIase activity or, more likely, PmpA foldase activity does not necessarily require PPIase activity.

Amino Acid Motifs↗
PubMed2003

Microarray analysis in the clinical management of cancer.

Because of the many genetic and epigenetic alterations that define a given tumor cell, and given the heterogeneity of these changes, between, as well as within a tumor class, progress in the understanding and treatment of cancer has been slow. The sequencing of the human genome, in combination with advances in robotics, computing, and imaging technologies, has resulted in rapid advances in the development of microarray methodology. This technology now places us in a position to simultaneously consider the consequence of all of these genetic changes through measurement of a large proportion of the complement of genes expressed in a given tissue at a given time. The power of this methodology for (1) the classification and identification of tumor classes, (2) gene discovery, (3) determining mechanisms of drug action, and (4) predicting drug response has now clearly been demonstrated: however, several challenges remain. First, there is a growing need for a standardization of the methodology, such that different datasets may be compared directly and meaningfully. The complete sequencing and annotation of the human genome may be the first step toward this attainable goal. Also, the databases generated should be made publicly available to facilitate further analysis by other researchers. To this end, the results of our studies are available at http://sequence.aecom.yu.edu/bioinf/Augenlicht/default.html. Second, a number of reported findings on tumor classification require further validation in independent patient data sets. Third, extensive clinical studies with appropriate patient follow-up are required to determine the validity of this method for the prediction of patient response to chemotherapy. Finally, the possibility needs to be considered that gene expression profiling may need to be combined with other global approaches such as proteomics and mutation screening analyses, for optimization of its potential. The advent of methodologies that enable gene expression profiling provides an opportunity to gain insights into the genetic makeup of a cancer cell on a global scale. Given the heterogeneity of this disease, such a global approach is likely to enhance significantly our understanding and management of this disease.

Gene Expression Profiling↗
PubMed2001

From PREDs and open reading frames to cDNA isolation: revisiting the human chromosome 21 transcription map.

A supernumerary copy of human chromosome 21 (HC21) causes Down syndrome. To understand the molecular pathogenesis of Down syndrome, it is necessary to identify all HC21 genes. The first annotation of the sequence of 21q confirmed 127 genes, and predicted an additional 98 previously unknown "anonymous" genes (predictions (PREDs) and open reading frames (C21orfs)), which were foreseen by exon prediction programs and/or spliced expressed sequence tags. These putative gene models still need to be confirmed as bona fide transcripts. Here we report the characterization and expression pattern of the putative transcripts C21orf7, C21orf11, C21orf15, C21orf18, C21orf19, C21orf22, C21orf42, C21orf50, C21orf51, C21orf57, and C21orf58, the GC-rich sequence DNA-binding factor candidate GCFC (also known as C21orf66), PRED12, PRED31, PRED34, PRED44, PRED54, and PRED56. Our analysis showed that most of the C21orfs originally defined by matching spliced expressed sequence tags were correctly predicted, whereas many of the PREDs, defined solely by computer prediction, do not correspond to genuine genes. Four of the six PREDs were incorrectly predicted: PRED44 and C21orf11 are portions of the same transcript, PRED31 is a pseudogene, and PRED54 and PRED56 were wrongly predicted. In contrast, PRED12 (now called C21orf68) and PRED34 (C21orf63) are now confirmed transcripts. We identified three new genes, C21orf67, C21orf69, and C21orf70, not previously predicted by any programs. This revision of the HC21 transcriptome has consequences for the entire genome regarding the quality of previous annotations and the total number of transcripts. It also provides new candidates for genes involved in Down syndrome and other genetic disorders that map to HC21.

Animals↗
PubMed2026

A tunable, ultrasensitive threshold in enzymatic activity governs the DNA methylation landscape.

DNA methylation is a widely studied epigenetic mark, affecting gene expression and cellular function at multiple levels. DNA methylation in the mammalian genome occurs primarily at cytosine-phosphate-guanine (CpG) dinucleotides, and patterning of the methylation landscape (i.e., the presence or absence of CpG methylation at a given genomic location) exhibits a generally bimodal distribution. Although much is known about the enzymatic writers and erasers of CpG methylation, it is not fully understood how these enzymes, along with genetic, chromatin, and regulatory factors, control the genome-wide methylation landscape. In this study, methylation is analyzed at annotated CpG islands (CGIs) and independent CpGs as a function of their proximity to other CpG substrates. Analysis is aided by a computationally efficient stochastic mathematical model of methylation dynamics, enabling parameterization from data. We find that methylation exhibits a switch-like dependence on local CpG density with a threshold of 7-8 CpGs per 100 bp and a Hill coefficient of 4-5. The threshold and steepness of the switch is modified in cell lines in which key enzymes are knocked out. Modeling further elucidates how enzymatic parameters, including catalytic rates and lengthscales of inter-CpG interaction, tune the properties of the switch. Together, the results support a model in which competition between opposing TET1-3 demethylating enzymes and DNA methyltransferases (DNMT3A/B) results in an ultrasensitive switch, analogous to the protein phosphorylation switch (termed "zero-order ultrasensitivity"). Our study provides insight to the mechanisms underlying establishment and maintenance of bimodal DNA methylation landscapes, and further provides a flexible pipeline for gleaning molecular insights to the cellular methylation machinery across cell-specific, epigenomic data sets.

DNA Methylation↗
PubMed2006

Identification of functional modules in a PPI network by clique percolation clustering.

Large-scale experiments and data integration have provided the opportunity to systematically analyze and comprehensively understand the topology of biological networks and biochemical processes in cells. Modular architecture which encompasses groups of genes/proteins involved in elementary biological functional units is a basic form of the organization of interacting proteins. Here we apply a graph clustering algorithm based on clique percolation clustering to detect overlapping network modules of a protein-protein interaction (PPI) network. Our analysis of the yeast Sacchromyces cerevisiae suggests that most of the detected modules correspond to one or more experimentally functional modules and half of these annotated modules match well with experimentally determined protein complexes. Our method of analysis can of course be applied to protein-protein interaction data for any species and even other biological networks.

Algorithms↗