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PubMed2026

Exploring genomic regions regulating the liver transcriptome and energy homeostasis in pigs.

In pigs, energy homeostasis has an impact on meat quality and health. In a Duroc pig population, 30 quantitative trait locus (QTL) regions associated with fatty acid (FA) composition in adipose tissue, plasma, liver and muscle were previously identified. Mapping of expression quantitative trait locus (eQTL) regions will provide a molecular hypothesis for genotype-phenotype interactions and may allow the identification of shared causal variants, key to increasing our understanding of the genetic regulation of FA composition and energy homeostasis. However, gene expression is impacted by environmental factors, while individual-level allelic imbalance (AI) can be more reliable and can be surveyed via allelic-specific expression (ASE) analysis. Furthermore, treatment of ASE as a quantitative trait allows the identification of allele-specific expression quantitative trait loci (aseQTLs), which are variants whose heterozygosity is linked to the AI of a nearby single-nucleotide polymorphism (SNP), pointing to regulatory elements. In this study, liver was selected as a key metabolic hub with an important role in the regulation of energy homeostasis, and 310 liver RNA sequencing samples were analysed using a combination of (1) eQTL mapping, (2) ASE analysis, and (3) aseQTL mapping methods. A total of 2 188 eQTL regions were identified, mostly cis-eQTL regions (73.17%). ASE analysis reported 1 964 ASE SNPs, associated with 633 genes. Finally, aseQTL mapping reported 64 172 aseQTL, associated with the AI of 31 genes. Colocalisation analysis combined with ASE analysis showed that the expression of FADS1 and FADS2 genes is associated with the polyunsaturated FA composition in several tissues, where microRNA regulation may be present. Finally, in the DGAT2 gene, annotated in a QTL region associated with multiple FAs in adipose tissue, ASE revealed allelic imbalance in the 3' untranslated region (UTR) of this gene. Allelic differential expression can be caused by a 13-bp insertion affecting messenger RNA stability, previously described, exemplifying how allelic imbalance is caused by a post-transcriptional regulatory mechanism undetectable by eQTL mapping. Furthermore, aseQTLs were associated with this gene, linked to a previously identified copy number variant not yet associated with DGAT2 expression. These results demonstrate how ASE analysis and aseQTL mapping can complement eQTL mapping, as they resolved a complex region affected by allelic heterogeneity, a main confounding effect of QTL mapping. In conclusion, the combination of eQTL mapping, ASE analysis and aseQTL mapping allowed the characterisation of the regulation of liver gene expression, improving our understanding of the genetic determinism of energy homeostasis.

Allele-specific expression↗
PubMed2004

Identification of changes in the transcriptome profile of human hepatoma HepG2 cells stimulated with interleukin-1 beta.

Interleukin-1 (IL-1) is the principal pro-inflammatory cytokine participating in the initiation of acute phase response. Human hepatoma HepG2 cells were exposed to 15 ng/ml of IL-1beta for times ranging from 1 to 24 h and the total RNA was isolated. Then cDNA was obtained and used for differential display with 10 arbitrary primers and 9 oligo(dT) primers designed by Clontech. Validation of observed changes of differentially expressed known genes was carried out by RT-PCR or Northern blot analysis. Out of 90 cDNA strands modulated by IL-1, 46 have been successfully reamplified and their sequencing indicates that they represent 36 different cDNA templates. By GenBank search, 26 cDNA clones were identified as already known genes while 10 showed no homology to any known gene. The identified transcripts modulated by IL-1 in HepG2 cells code for intracellular proteins of various function: trafficking/motor proteins (3 genes), proteins participating in the translation machinery or posttranscriptional/posttranslational modifications (7 genes), proteases (1 gene), proteins involved in metabolism (6 genes), activity modulators (3 genes), proteins of the cell cycle machinery (2 genes) and those functionally unclassified (4 genes). Majority of genes responded to IL-1 within 1 to 6 h (early genes), while two were late response genes (12-24 h) and four showed prolonged response over the whole 24-h period. Most of the observed changes of expression were in the range of two- to threefold increase in comparison to control untreated cells. Among identified genes, no typical secretory acute phase protein was found. The obtained results suggest that IL-1 affects the expression of several genes in HepG2 cells, especially those engaged in the synthesis and modifications of proteins.

Carcinoma, Hepatocellular↗
PubMed2005

Beta-carotene and the application of transcriptomics in risk-benefit evaluation of natural dietary components.

Beta-carotene is a natural food component that is present in fruits and vegetables and is also used as a food colorant and a supplement. Beta-carotene is an anti-oxidant and a source of vitamin A. It is endowed with health beneficial properties, but a number of studies showed that with high intakes it may increase the risk for lung cancer in at risk individuals (heavy smokers, asbestos workers and alcohol users). To establish the window of benefit, it is necessary to identify early markers of effect and to obtain insight in the mechanism of action of beta-carotene, in the absence and presence of environmental risk factors. Genomics technologies are well suited to dissect the mechanisms of action and identify the markers of effect. Human cell lines can be used to analyse the effects of beta-carotene, but exposure studies with beta-carotene show that cell lines display a widely variant behaviour, which hampers translation to the in vivo situation in humans. Alternatively, animal studies can be used. Especially the ferret seems to be a good model, but little sequence information of this species is available. However, heterologous hybridization on human cDNA seems possible and provides and a new tool for molecular analysis of health effects of beta-carotene.

Animals↗
PubMed2006

Transcriptome analysis of fetal metatarsal long bones by microarray, as a model for endochondral bone formation.

Endochondral bone formation is orchestrated by mesenchymal cell condensation to form cartilage anlagen, which act as a template for bone formation and eventual mineralization. The current study performed gene expression analysis to examine pre- and post-mineralization stages (E15 and E19) of endochondral bone formation, using fetal metatarsal long bones as a model. An extensive number of genes were differentially expressed, with 543 transcripts found to have at least 2-fold up-regulation and 742 with a greater than 2-fold down-regulation. A bioinformatics approach was adopted based on gene ontology groups, and this identified genes associated with the regulation of signaling and skeletal development, cartilage replacement by bone, and matrix degradation and turnover. Transcripts linked to skeletal patterning, including Hoxd genes 10-12, Gli2 and Noggin were considerably down-regulated at E19. Whereas genes associated with bone matrix formation and turnover, ACP5, MMP-13, bone sialoprotein, osteopontin, dentin matrix protein-1 and MMP-9 all were distinctly up-regulated at this later time point. This approach to studying the formation of the primary ossification center provides a unique picture of the developmental dynamics involved in the molecular and biochemical processes during this intricately regulated process.

Animals↗
PubMed2004

Sensitivity of the brain transcriptome to connexin ablation.

Extensive studies on mice with total or partial disruption of either connexin43 (Cx43) or connexin32 (Cx32) have detected only subtle changes in central nervous system structure, growth, development, or function. We have used high density cDNA arrays to analyze the regulation, control, and coordination of the abundances of 7446 distinct transcripts in four brains, each of Cx43 null (K43), Cx43 heterozygous (H43), and Cx32 null (K32) mice as compared to the brains of wildtype (W) mice. The use of multiple samples allowed the determination of the statistical significance of gene regulation. Significantly regulated genes encoded proteins of all functional categories, extending beyond those that might be expected to depend on junctional communication. Moreover, we found a high degree of similarity between genes regulated in the K43 and H43 brains and a remarkable overlap between gene regulation in brains of K43 and K32. The regulated genes in both K43 and H43 brains showed an outstanding inverse coordination with the levels of expression of Cx43 in W brain, indicating that the regulated genes are largely predictable from their co-variance with Cx43 in the wildtype samples. These findings lead to the hypothesis that connexin expression may represent a central node in the regulation of gene expression patterns in brain.

Animals↗
PubMed2004

Response of rainbow trout transcriptome to model chemical contaminants.

We used high-density cDNA microarray in studies of responses of rainbow trout fry at sublethal ranges of beta-naphthoflavone, cadmium, carbon tetrachloride, and pyrene. The differentially expressed genes were grouped by the functional categories of Gene Ontology. Significantly different response to the studied compounds was shown by a number of classes, such as cell cycle, apoptosis, signal transduction, oxidative stress, subcellular and extracellular structures, protein biosynthesis, and modification. Cluster analysis separated responses to the contaminants at low and medium doses, whereas at high levels the adaptive reactions were masked with general unspecific response to toxicity. We found enhanced expression of many mitochondrial proteins as well as genes involved in metabolism of metal ions and protein biosynthesis. In parallel, genes related to stress and immune response, signal transduction, and nucleotide metabolism were down-regulated. We performed computer-assisted analyses of Medline abstracts retrieved for each compound, which helped us to indicate the expected and novel findings.

Animals↗
PubMed2004

Transcriptome and proteome expression in activated human CD4 and CD8 T-lymphocytes.

T-lymphocytes (T-cells) are unique in that unlike monocytes, they have no insulin receptors, and are insulin insensitive, but upon activation with antigens develop insulin, IGF-1, and IL-2 receptors, and become insulin sensitive tissues. In vivo activation of these cells has now been demonstrated in patients with diabetic ketoacidosis. We analyzed the genomics and proteomics of activated and non-activated CD4+ and CD8+ T-cells of normal subjects using Affymetrix microarray gene chips and proteomes by SELDI-TOF mass spectrometry analysis. Genes for IL-2, insulin, and IGF-1 receptors were increased at least 2-fold in activated vs non-activated T-cells. Using an expression array containing the entire human genome of 39,500 genes, we evaluated approximately 27,000 genes relevant in physiologic and cellular ontologies. Of these, approximately 10,500 genes were increased in activated cells, compared to about 7,000, which were decreased, and approximately 9500, which were unchanged. Among activated ontologies were signal transduction pathways such as IRS-1, IRS-2, Akt, and glycolytic pathways. To our knowledge this is the first report of an hitherto unreported event. Possible implications of these processes are discussed in the light of their physiological significance.

Adult↗
PubMed2005

Correlation of codon bias measures with mRNA levels: analysis of transcriptome data from Escherichia coli.

Although codon usage is often represented by a 61-dimensional vector, the ability of determining the codon bias in a gene relies on a uni-dimensional vector which measures the total bias in usage of synonymous codons. Codon usage is receiving more and more focus because codon biases might be valuable tools to predict and optimize gene/protein expression. How good any of these measures is for correlating codon usage with gene and protein expression has yet to be investigated. In this study, we correlated gene transcript levels in Escherichia coli with codon usage, using a number of different codon bias measures. We found that there is a significant correlation between transcript levels and codon bias measures, suggesting that these measures can be used to assess or predict gene expression. The codon bias measure performing best in this context was the codon adaptation index.

Codon↗
PubMed2005

Transcriptome analysis in the midgut of the earthworm (Eisenia andrei) using expressed sequence tags.

In order to gain insight into the expression profiles of the earthworm midgut, we analyzed 1106 expressed sequence tags (ESTs) derived from the earthworm midgut cDNA library. Among the 1106 ESTs analyzed, 557 (50.4%) ESTs showed significant similarity to known genes and represented 229 unique genes of which 166 ESTs were singletons and 63 ESTs manifest as two or more ESTs. While 552 ESTs (49.9%) were sequenced only once, 230 ESTs (20.8%) appeared two to five times and 324 ESTs (29.3%) were sequenced more than five times. Considering this redundancy of expression, it is likely that the gene expression profile of the earthworm midgut would be polarized. The expression of globin-related proteins, including ferritin and linker chain, and fibrinolytic enzymes appeared to account for 10.1% and 4.7% of the total ESTs analyzed in this study, respectively. This suggests that the prime functions of the midgut in the earthworm would be associated with protein hydrolysis as well as globin formation. Among the recognized protein-coding genes, the gene category involved in protein synthesis appeared to be the largest one accounting for 15.6% of the expression in the midgut, followed by gene categories associated with energy (11.2%), homeostasis (10.8%), metabolism (3.6%), cytoskeleton (2.5%), and protein fate (1.4%). With regard to functional aspects, the most abundantly expressed genes were associated with respiratory pigment (10.1%), cellular respiration (8.6%), and fibrin hydrolysis (4.7%). In addition, we were able to identify novel ESTs in the earthworm, which were related to the innate immune system, including destabilase, a possible antagonist of transglutaminase.

Animals↗
PubMed2006

Transcriptomic changes in developing kidney exposed to chronic hypoxia.

cDNA arrays compared gene expression in kidneys of neonatal mice subjected to 1, 2, and 4 weeks of chronic constant (CCH) or intermittent (CIH) hypoxia with normoxic littermates. Five to twenty percent of genes were regulated in each condition, with greater changes in CCH. Up-regulation of 42% of the solute carriers after 1 week of CCH suggests a strong activation of pH controlling pathways. Significant reduction in expression change of genes important in growth, development, and aging as a function of time indicates reduced maturation rate in CIH and CCH treatments. Regulated genes showed gender dependence in CCH, being higher in females than males at 1 week and higher in males than females thereafter. Transcriptional control was enhanced in CCH but not in CIH. Thus, CCH and CIH both alter gene expression and retard maturation with the more profound changes occurring in CCH than in CIH.

Aging↗
PubMed2004

Analysis of Bothrops jararacussu venomous gland transcriptome focusing on structural and functional aspects: I--gene expression profile of highly expressed phospholipases A2.

Snake venom glands are a rich source of bioactive molecules such as peptides, proteins and enzymes that show important pharmacological activity leading to in local and systemic effects as pain, edema, bleeding and muscle necrosis. Most studies on pharmacologically active peptides and proteins from snake venoms have been concerned with isolation and structure elucidation through methods of classical biochemistry. As an attempt to examine the transcripts expressed in the venom gland of Bothrops jararacussu and to unveil the toxicological and pharmacological potential of its products at the molecular level, we generated 549 expressed sequence tags (ESTs) from a directional cDNA library. Sequences obtained from single-pass sequencing of randomly selected cDNA clones could be identified by similarities searches on existing databases, resulting in 197 sequences with significant similarity to phospholipase A(2) (PLA(2)), of which 83.2% were Lys49-PLA(2) homologs (BOJU-I), 0.1% were basic Asp49-PLA(2)s (BOJU-II) and 0.6% were acidic Asp49-PLA(2)s (BOJU-III). Adjoining this very abundant class of proteins we found 88 transcripts codifying for putative sequences of metalloproteases, which after clustering and assembling resulted in three full-length sequences: BOJUMET-I, BOJUMET-II and BOJUMET-III; as well as 25 transcripts related to C-type lectin like protein including a full-length cDNA of a putative galactose binding C-type lectin and a cluster of eight serine-proteases transcripts including a full-length cDNA of a putative serine protease. Among the full-length sequenced clones we identified a nerve growth factor (Bj-NGF) with 92% identity with a human NGF (NGHUBM) and an acidic phospholipase A(2) (BthA-I-PLA(2)) displaying 85-93% identity with other snake venom toxins. Genetic distance among PLA(2)s from Bothrops species were evaluated by phylogenetic analysis. Furthermore, analysis of full-length putative Lys49-PLA(2) through molecular modeling showed conserved structural domains, allowing the characterization of those proteins as group II PLA(2)s. The constructed cDNA library provides molecular clones harboring sequences that can be used to probe directly the genetic material from gland venom of other snake species. Expression of complete cDNAs or their modified derivatives will be useful for elucidation of the structure-function relationships of these toxins and peptides of biotechnological interest.

Amino Acid Sequence↗
PubMed2005

Transcriptomics applied to obesity and caloric restriction.

Caloric restriction still remains the most efficient way to promote weight loss. Deciphering the molecular basis of adaptation to energy restriction is critical for the tailoring of new therapeutic strategies. This review focuses on the recent input of gene profiling on adipose tissue in obesity pathogenesis and on the new insights on adaptations occurring during very low caloric diet (VLCD) in humans. Hypocaloric diets improve a wide range of metabolic parameters including lipolytic efficiency, insulin sensitivity, and inflammatory profile. In the subcutaneous white adipose tissue (scWAT) the VLCD induced a decrease in the mRNA levels for the antilipolytic alpha2-adrenergic receptor associated with changes in catecholamine-induced adipocyte lipolytic capacity. The improvement in insulin sensitivity was not associated with a change in subcutaneous adipose tissue adiponectin gene expression or in its plasma level, suggesting that adiponectin is not involved in the regulation of VLCD-induced improvement of insulin sensitivity and that there is a small contribution of subcutaneous adipose tissue to plasma adiponectin levels. Pangenomic microarray studies in human scWAT revealed that a panel of inflammatory markers and acute phase reactants were over expressed in obese compared to lean subjects. Caloric restriction improved the inflammatory profile of obese subjects through a decrease of pro-inflammatory factors and an increase of anti-inflammatory molecules. These genes were mostly expressed in the stroma vascular fraction of the adipose tissue. Specific cell-type isolation and immunohistochemistry demonstrated that monocyte/macrophage lineage cells were responsible for the expression of both mRNA and protein inflammatory markers. The acute phase proteins serum amyloid A was highly expressed in mature adipocytes from obese subjects. Caloric restriction decreased both serum amyloid mRNA and circulating levels. Obesity now clearly appears as chronic low-grade inflammation state. Modulation of the inflammatory pathways may represent new therapeutic targets for the treatment of obesity-related complications.

Adipose Tissue↗
PubMed2006

Transcriptome analysis of expressed sequence tags from the venom glands of the fish Thalassophryne nattereri.

Thalassophryne nattereri (niquim) is a venomous fish found on the northern and northeastern coasts of Brazil. Every year, hundreds of humans are affected by the poison, which causes excruciating local pain, edema, and necrosis, and can lead to permanent disabilities. In experimental models, T. nattereri venom induces edema and nociception, which are correlated to human symptoms and dependent on venom kininogenase activity; myotoxicity; impairment of blood flow; platelet lysis and cytotoxicity on endothelial cells. These effects were observed with minute amounts of venom. To characterize the primary structure of T. nattereri venom toxins, a list of transcripts within the venom gland was made using the expressed sequence tag (EST) strategy. Here we report the analysis of 775 ESTs that were obtained from a directional cDNA library of T. nattereri venom gland. Of these ESTs, 527 (68%) were related to sequences previously described. These were categorized into 10 groups according to their biological functions. Sequences involved in gene and protein expression accounted for 14.3% of the ESTs, reflecting the important role of protein synthesis in this gland. Other groups included proteins engaged in the assembly of disulfide bonds (0.5%), chaperones involved in the folding of nascent proteins (1.4%), and sequences related to clusterin (1.5%), as well as transcripts related to calcium binding proteins (1.0%). We detected a large cluster (1.3%) related to cocaine- and amphetamine-regulated transcript (CART), a peptide involved in the regulation of food intake. Surprisingly, several retrotransposon-like sequences (1.0%) were found in the library. It may be that their presence accounts for some of the variation in venom toxins. The toxin category (18.8%) included natterins (18%), which are a new group of kininogenases recently described by our group, and a group of C-type lectins (0.8%). In addition, a considerable number of sequences (32%) was not related to sequences in the databases, which indicates that a great number of new toxins and proteins are still to be discovered from this fish venom gland.

Amino Acid Sequence↗
PubMed2006

Genome-wide transcriptome profiling of the early cadmium response of Arabidopsis roots and shoots.

Transcriptional regulation in response to cadmium treatment was investigated in both roots and leaves of Arabidopsis, using the whole genome CATMA microarray containing at least 24,576 independent probe sets. Arabidopsis plants were hydroponically treated with low (5 microM) or high (50 microM) cadmium concentrations during 2, 6, and 30 hours. At each time point, Cd level was determined using ICP-AES showing that both plant tissues are able to accumulate the heavy metal. RT-PCR of eight randomly selected genes confirmed the reliability of our microarray results. Analyses of response profiles demonstrate the existence of a regulatory network that differentially modulates gene expression in a tissue- and kinetic-specific manner in response to cadmium. One of the main response observed in roots was the induction of genes involved in sulfur assimilation-reduction and glutathione (GSH) metabolism. In addition, HPLC analysis of GSH and phytochelatin (PC) content shows a transient decrease of GSH after 2 and 6 h of metal treatment in roots correlated with an increase of PC contents. Altogether, our results suggest that to cope with cadmium, plants activate the sulfur assimilation pathway by increasing transcription of related genes to provide an enhanced supply of GSH for PC biosynthesis. Interestingly, in leaves an early induction of several genes encoding enzymes involved in the biosynthesis of phenylpropanoids was observed. Finally, our results provide new insights to understand the molecular mechanisms involved in transcriptional regulation in response to cadmium exposure in plants.

Arabidopsis↗
PubMed2006

Global survey of organ and organelle protein expression in mouse: combined proteomic and transcriptomic profiling.

Organs and organelles represent core biological systems in mammals, but the diversity in protein composition remains unclear. Here, we combine subcellular fractionation with exhaustive tandem mass spectrometry-based shotgun sequencing to examine the protein content of four major organellar compartments (cytosol, membranes [microsomes], mitochondria, and nuclei) in six organs (brain, heart, kidney, liver, lung, and placenta) of the laboratory mouse, Mus musculus. Using rigorous statistical filtering and machine-learning methods, the subcellular localization of 3274 of the 4768 proteins identified was determined with high confidence, including 1503 previously uncharacterized factors, while tissue selectivity was evaluated by comparison to previously reported mRNA expression patterns. This molecular compendium, fully accessible via a searchable web-browser interface, serves as a reliable reference of the expressed tissue and organelle proteomes of a leading model mammal.

Animals↗
PubMed2006

Molecular characterization of the developmental gene in eyes: through data-mining on integrated transcriptome databases.

OBJECTIVES: Our aim was to utilize publicly available and proprietary sources to discover candidate genes important for ocular development. DESIGN AND METHODS: The collated information on our 5092 non-redundant clusters was grouped and functional annotation was conducted using gene ontology (FatiGO) for categorizing them with respect to molecular function. The web-based viewer technological platform (H-InvDB) was employed for transcription analyses of in-house high quality fetal eye Expressed Sequence Tags (ESTs). Eye-specific ESTs were also analyzed across species by using EMBEST. RESULTS: According to adult eye cDNA libraries, nucleic acid binding and cell structure/cytoskeletal protein genes were the most abundant among the ESTs of fetal eyes. Using cDNA assembly in H-InvDB, 20 (80%) of the 25 most commonly expressed genes in the human eye are also expressed in extraocular tissues. The crystalline gamma S gene is highly expressed in the eye, but not in other tissues. We used EMBEST to compare human fetal eye and octopus eye ESTs and the expression similarity was low (1.6%). This indicated that our fetal eye library contains genes necessary for the developmental process and biological function of the eye, which may not be expressed in the fully developed octopus eyes. The human fetal eye cDNA library also contained highly abundant eye tissue genes, including alphaA-crystallin, eukaryotic translation elongation factor 1 alpha 1 (EEF1A1), bestrophin (VMD2), cystatin C, and transforming growth factor, beta-induced (BIGH3). CONCLUSIONS: Our annotated EST set provides a valuable resource for gene discovery and functional genomic analysis. This display will help to appreciate the strengths and weaknesses of the different technological platforms, so that in future studies the maximum amount of beneficial information can be derived from the appropriate use of each method.

Animals↗