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Transcriptional Profiling of Aging in Human Muscle Reveals a Common Aging Signature  [PDF]
Jacob M Zahn,Rebecca Sonu,Hannes Vogel,Emily Crane,Krystyna Mazan-Mamczarz,Ralph Rabkin,Ronald W Davis,Kevin G Becker,Art B Owen,Stuart K Kim
PLOS Genetics , 2006, DOI: 10.1371/journal.pgen.0020115
Abstract: We analyzed expression of 81 normal muscle samples from humans of varying ages, and have identified a molecular profile for aging consisting of 250 age-regulated genes. This molecular profile correlates not only with chronological age but also with a measure of physiological age. We compared the transcriptional profile of muscle aging to previous transcriptional profiles of aging in the kidney and the brain, and found a common signature for aging in these diverse human tissues. The common aging signature consists of six genetic pathways; four pathways increase expression with age (genes in the extracellular matrix, genes involved in cell growth, genes encoding factors involved in complement activation, and genes encoding components of the cytosolic ribosome), while two pathways decrease expression with age (genes involved in chloride transport and genes encoding subunits of the mitochondrial electron transport chain). We also compared transcriptional profiles of aging in humans to those of the mouse and fly, and found that the electron transport chain pathway decreases expression with age in all three organisms, suggesting that this may be a public marker for aging across species.
Transcriptional profiling of MnSOD-mediated lifespan extension in Drosophila reveals a species-general network of aging and metabolic genes
Christina Curtis, Gary N Landis, Donna Folk, Nancy B Wehr, Nicholas Hoe, Morris Waskar, Diana Abdueva, Dmitriy Skvortsov, Daniel Ford, Allan Luu, Ananth Badrinath, Rodney L Levine, Timothy J Bradley, Simon Tavaré, John Tower
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-12-r262
Abstract: A doxycycline-regulated system was used to over-express manganese-SOD (MnSOD) in adult Drosophila, yielding increases in mean and maximal lifespan of 20%. Increased lifespan resulted from lowered initial mortality rate and required MnSOD over-expression in the adult. Transcriptional profiling indicated that the expression of specific genes was altered by MnSOD in a manner opposite to their pattern during normal aging, revealing a set of candidate biomarkers of aging enriched for carbohydrate metabolism and electron transport genes and suggesting a true delay in physiological aging, rather than a novel phenotype. Strikingly, cross-dataset comparisons indicated that the pattern of gene expression caused by MnSOD was similar to that observed in long-lived Caenorhabditis elegans insulin-like signaling mutants and to the xenobiotic stress response, thus exposing potential conserved longevity promoting genes and implicating detoxification in Drosophila longevity.The data suggest that MnSOD up-regulation and a retrograde signal of reactive oxygen species from the mitochondria normally function as an intermediate step in the extension of lifespan caused by reduced insulin-like signaling in various species. The results implicate a species-conserved net of coordinated genes that affect the rate of senescence by modulating energetic efficiency, purine biosynthesis, apoptotic pathways, endocrine signals, and the detoxification and excretion of metabolites.Reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radical are produced as byproducts of normal cellular metabolism. These ROS, especially hydrogen peroxide, are participants in cellular signaling pathways [1]. In addition, ROS can damage macromolecules and this process is implicated in human aging and disease [2]. Among the most important regulators of ROS levels are the superoxide dismutase (SOD) enzymes [3,4]: Cu/ZnSOD in the cytoplasm and outer mitochondrial space, and MnSOD exclusively in th
Cellular transcriptional profiling in human lung epithelial cells infected by different subtypes of influenza A viruses reveals an overall down-regulation of the host p53 pathway
Olivier Terrier, Laurence Josset, Julien Textoris, Virginie Marcel, Ga?lle Cartet, Olivier Ferraris, Catherine N'Guyen, Bruno Lina, Jean-Jacques Diaz, Jean-Christophe Bourdon, Manuel Rosa-Calatrava
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-285
Abstract: Our results were supported by both RT-qPCR and western blot analyses and reveal multiple alterations of the p53 pathway during infection. A down-regulation of mRNA expression was observed for the main regulators of p53 protein stability during infection by the complete set of viruses tested, and a significant decrease in p53 mRNA expression was also observed in H5N1 infected cells. In addition, several p53 target genes were also down-regulated by these influenza viruses and the expression of their product reduced.Our data reveal that influenza viruses cause an overall down-regulation of the host p53 pathway and highlight this pathway and p53 protein itself as important viral targets in the altering of apoptotic processes and in cell-cycle regulation.Influenza viruses belong to the Orthomyxoviridae family of enveloped viruses containing a segmented genome of single stranded negative RNA. Among the three influenza types (A, B and C), type A is the most virulent pathogen with a diversity represented by the combination of 16 H and 9 N different subtypes (e.g. H1N1, H5N1) [1]. Influenza A viruses are the most serious threat to public health, with the potential to cause global pandemics as was illustrated in 2009 with the emergence of H1N1 SOIV [2].All known subtypes of the influenza A virus are maintained in wild waterfowl, the natural reservoir of these viruses [3]. Current human circulating influenza A subtypes are H1N1 and H3N2. While extensive viral diversity is responsible for the subtype-specific virus-host interactions, many common functional features are also shared among viruses. Influenza infection alters host cellular homeostasis via the combination of the virally-induced alteration of biological machineries/pathways and the cellular antiviral response triggered by intracellular signalling cascades. Influenza viruses are able to activate/inhibit and hijack several cellular signalling pathways to efficiently support their own replication [4].The development of
Transcriptional profiling reveals multifunctional roles for transferrin in the honeybee, Apis mellifera
R. Kucharski,R. Maleszka
Journal of Insect Science , 2003,
Abstract: Transferrins belong to a family of iron-binding proteins that have been implicated in innate immunity and in vitellogenesis in insects. Here we have sequenced and characterized a full-length cDNA encoding a putative iron-binding transferrin (AmTRF) in the honeybee. AmTRF shows high level of sequence identity with transferrins in both vertebrates and insects (26-46%) suggesting that the primary function of the predicted 712 amino acid protein is binding and transporting of iron. AmTRF is expressed ubiquitously, but particularly high levels of its mRNA are found in the central brain and in the compound eye. Using northern blotting and a microarray based approach we have examined the levels of AmTRF mRNA by expression profiling under a wide range of conditions including developmental stages, septic injury and juvenile hormone treatment. Increased expression of AmTRF is seen during early pupal stages, in the brain of mature foragers and in the abdomen of virgin queens, whereas treatment with juvenile hormone leads to a decrease of AmTRF levels in the abdomen. We show that a transcriptional response of transferrin to septic injury with E. coli is relatively moderate as compared to a dramatic up-regulation of an antibacterial polypeptide, Hymenoptaecin, under similar conditions. We conclude that major fluctuations of AmTRF mRNA in time and space are consistent with context-dependent functional significance and suggest broader multifunctional roles for transferrin in insects.
Transcriptional profiling in C. elegans suggests DNA damage dependent apoptosis as an ancient function of the p53 family
Sebastian Greiss, Bj?rn Schumacher, Kaj Grandien, Jonathan Rothblatt, Anton Gartner
BMC Genomics , 2008, DOI: 10.1186/1471-2164-9-334
Abstract: Examining C. elegans expression profiles using whole genome Affymetrix GeneChip arrays, we found that 83 genes were induced more than two fold upon ionizing radiation (IR). None of these genes, with exception of an ATP ribosylase homolog, encode for known DNA repair genes. Using two independent cep-1 loss of function alleles we did not find genes regulated by cep-1 in the absence of IR. Among the IR-induced genes only three are dependent on cep-1, namely egl-1, ced-13 and a novel C. elegans specific gene. The majority of IR-induced genes appear to be involved in general stress responses, and qRT-PCR experiments indicate that they are mainly expressed in somatic tissues. Interestingly, we reveal an extensive overlap of gene expression changes occurring in response to DNA damage and in response to bacterial infection. Furthermore, many genes induced by IR are also transcriptionally regulated in longevity mutants suggesting that DNA damage and aging induce an overlapping stress response.We performed genome-wide gene expression analyses which indicate that only a surprisingly small number of genes are regulated by CEP-1 and that DNA damage induced apoptosis via the transcriptional induction of BH3 domain proteins is likely to be an ancient DNA damage response function of the p53 family. Interestingly, although the apoptotic response to DNA damage is regulated through the transcriptional activity of CEP-1, other DNA damage responses do not appear to be regulated on the transcriptional level and do not require the p53 like gene cep-1.Previous studies established the C. elegans system as a simple multicellular organism to study DNA damage responses and DNA damage induced apoptosis. These studies led to the identification of a core C. elegans DNA damage response pathway that includes conserved upstream DNA damage sensor molecules such as the PI3 kinase-like ATM and ATR (Ce-ATL-1) kinases, the Rad-17 clamp loader-like molecule and the Rad-9-Hus-1-Rad-1(Ce-MRT-2) (9-1-1) repl
Sequential Use of Transcriptional Profiling, Expression Quantitative Trait Mapping, and Gene Association Implicates MMP20 in Human Kidney Aging  [PDF]
Heather E. Wheeler,E. Jeffrey Metter,Toshiko Tanaka,Devin Absher,John Higgins,Jacob M. Zahn,Julie Wilhelmy,Ronald W. Davis,Andrew Singleton,Richard M. Myers,Luigi Ferrucci,Stuart K. Kim
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000685
Abstract: Kidneys age at different rates, such that some people show little or no effects of aging whereas others show rapid functional decline. We sequentially used transcriptional profiling and expression quantitative trait loci (eQTL) mapping to narrow down which genes to test for association with kidney aging. We first performed whole-genome transcriptional profiling to find 630 genes that change expression with age in the kidney. Using two methods to detect eQTLs, we found 101 of these age-regulated genes contain expression-associated SNPs. We tested the eQTLs for association with kidney aging, measured by glomerular filtration rate (GFR) using combined data from the Baltimore Longitudinal Study of Aging (BLSA) and the InCHIANTI study. We found a SNP association (rs1711437 in MMP20) with kidney aging (uncorrected p = 3.6×10?5, empirical p = 0.01) that explains 1%–2% of the variance in GFR among individuals. The results of this sequential analysis may provide the first evidence for a gene association with kidney aging in humans.
Transcriptional profiling reveals barcode-like toxicogenomic responses in the zebrafish embryo
Lixin Yang, Jules R Kemadjou, Christian Zinsmeister, Matthias Bauer, Jessica Legradi, Ferenc Müller, Michael Pankratz, Jens J?kel, Uwe Str?hle
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-10-r227
Abstract: We exposed zebrafish embryos to a range of environmental toxicants and measured the changes in gene-expression profiles by hybridizing cDNA to an oligonucleotide microarray. Several hundred genes responded significantly to at least one of the 11 toxicants tested. We obtained specific expression profiles for each of the chemicals and could predict the identity of the toxicant from the expression profiles with high probability. Changes in gene expression were observed at toxicant concentrations that did not cause morphological effects. The toxicogenomic profiles were highly stage specific and we detected tissue-specific gene responses, underscoring the sensitivity of the assay system.Our results show that the genome of the zebrafish embryo responds to toxicant exposure in a highly sensitive and specific manner. Our work provides proof-of-principle for the use of the zebrafish embryo as a toxicogenomic model and highlights its potential for systematic, large-scale analysis of the effects of chemicals on the developing vertebrate embryo.Organisms are open systems that are in constant exchange with their environment. As a consequence, living systems have to adapt to environmental conditions by adjusting their physiology accordingly. Chemicals from natural sources or manmade pollution can represent rather adverse environmental conditions with a fatal outcome if the organism fails to adapt. It is a well-established fact that xenobiotics such as dioxin or cadmium can induce changes in gene expression [1-3]. The responsive genes include adaptive genes that are involved in detoxification or protection against oxidative or other cellular stresses and may also comprise genes that are directly responsible for the fatal effects of the toxicants. The early life stages of vertebrates are generally the most susceptible to adverse chemical impact [4]. Yet we do not have a detailed picture of the transcriptional response profiles of these early life stages.There is a high demand by re
Transcriptional Profiling of Chondrodysplasia Growth Plate Cartilage Reveals Adaptive ER-Stress Networks That Allow Survival but Disrupt Hypertrophy  [PDF]
Trevor L. Cameron, Katrina M. Bell, Liliana Tatarczuch, Eleanor J. Mackie, M. Helen Rajpar, Ben T. McDermott, Raymond P. Boot-Handford, John F. Bateman
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024600
Abstract: Metaphyseal chondrodysplasia, Schmid type (MCDS) is characterized by mild short stature and growth plate hypertrophic zone expansion, and caused by collagen X mutations. We recently demonstrated the central importance of ER stress in the pathology of MCDS by recapitulating the disease phenotype by expressing misfolding forms of collagen X (Schmid) or thyroglobulin (Cog) in the hypertrophic zone. Here we characterize the Schmid and Cog ER stress signaling networks by transcriptional profiling of microdissected mutant and wildtype hypertrophic zones. Both models displayed similar unfolded protein responses (UPRs), involving activation of canonical ER stress sensors and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1 and Fgf21. Despite upregulation of the Chop/Cebpb pathway, apoptosis was not increased in mutant hypertrophic zones. Ultrastructural analysis of mutant growth plates revealed ER stress and disrupted chondrocyte maturation throughout mutant hypertrophic zones. This disruption was defined by profiling the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes. Our findings provide a transcriptional map of two chondrocyte UPR gene networks in vivo, and define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy. Thus they provide important insights into ER stress signaling and its impact on cartilage pathophysiology.
Ribosome profiling reveals post-transcriptional buffering of divergent gene expression in yeast  [PDF]
Joel McManus,Gemma May,Pieter Spealman,Alan Shteyman
Quantitative Biology , 2013,
Abstract: Understanding the patterns and causes of phenotypic divergence is a central goal in evolutionary biology. Much work has shown that mRNA abundance is highly variable between closely related species. However, the extent and mechanisms of post-transcriptional gene regulatory evolution are largely unknown. Here we used ribosome profiling to compare transcript abundance and translation efficiency in two closely related yeast species (S. cerevisiae and S. paradoxus). By comparing translation regulatory divergence to interspecies differences in mRNA sequence features, we show that differences in transcript leaders and codon bias substantially contribute to divergent translation. Globally, we find that translation regulatory divergence often buffers species-differences in mRNA abundance, such that ribosome occupancy is more conserved than transcript abundance. We used allele-specific ribosome profiling in interspecies hybrids to compare the relative contributions of cis- and trans-regulatory divergence to species differences in mRNA abundance and translation efficiency. The mode of gene regulatory divergence differs for these processes, as trans-regulatory changes play a greater role in divergent mRNA abundance than in divergent translation efficiency. Strikingly, most genes with aberrant transcript abundance in F1 hybrids (either over- or under-expressed compared to both parent species) did not exhibit aberrant ribosome occupancy. Our results show that interspecies differences in translation contribute substantially to the evolution of gene expression. Compensatory differences in transcript abundance and translation efficiency may increase the robustness of gene regulation.
Comprehensive transcriptional profiling of NaCl-stressed Arabidopsis roots reveals novel classes of responsive genes
Yuanqing Jiang, Michael K Deyholos
BMC Plant Biology , 2006, DOI: 10.1186/1471-2229-6-25
Abstract: We used microarrays of 70-mer oligonucleotide probes representing 23,686 Arabidopsis genes to identify root transcripts that changed in relative abundance following 6 h, 24 h, or 48 h of hydroponic exposure to 150 mM NaCl. Enrichment analysis identified groups of structurally or functionally related genes whose members were statistically over-represented among up- or down-regulated transcripts. Our results are consistent with generally observed stress response themes, and highlight potentially important roles for underappreciated gene families, including: several groups of transporters (e.g. MATE, LeOPT1-like); signalling molecules (e.g. PERK kinases, MLO-like receptors), carbohydrate active enzymes (e.g. XTH18), transcription factors (e.g. members of ZIM, WRKY, NAC), and other proteins (e.g. 4CL-like, COMT-like, LOB-Class 1). We verified the NaCl-inducible expression of selected transcription factors and other genes by qRT-PCR.Micorarray profiling of NaCl-treated Arabidopsis roots revealed dynamic changes in transcript abundance for at least 20% of the genome, including hundreds of transcription factors, kinases/phosphatases, hormone-related genes, and effectors of homeostasis, all of which highlight the complexity of this stress response. Our identification of these transcriptional responses, and groups of evolutionarily related genes with either similar or divergent transcriptional responses to stress, will facilitate mapping of regulatory networks and extend our ability to improve salt tolerance in plants.Roots are the primary site of perception and injury for several types of water-limiting stress, including salinity and drought. In many circumstances, it is the stress-sensitivity of the root that limits the productivity of the entire plant [1,2]. The physiological significance of roots is belied by their relative structural simplicity as compared to other plant organs: roots are largely lacking in some major metabolic pathways such as photosynthesis, and have
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