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Transcriptomic variation of pharmacogenes in multiple human tissues and lymphoblastoid cell lines.
Chhibber A, French CE, Yee SW, Gamazon ER, Theusch E, Qin X, Webb A, Papp AC, Wang A, Simmons CQ, Konkashbaev A, Chaudhry AS, Mitchel K, Stryke D, Ferrin TE, Weiss ST, Kroetz DL, Sadee W, Nickerson DA, Krauss RM, George AL, Schuetz EG, Medina MW, Cox NJ, Scherer SE, Giacomini KM, Brenner SE
(2017) Pharmacogenomics J 17: 137-145
MeSH Terms: Adipose Tissue, Alternative Splicing, Cell Line, Computational Biology, Databases, Genetic, Genotype, High-Throughput Nucleotide Sequencing, Humans, Kidney, Liver, Myocardium, Pharmacogenetics, Pharmacogenomic Variants, Phenotype, Sequence Analysis, RNA, Transcriptome
Show Abstract · Added February 22, 2016
Variation in the expression level and activity of genes involved in drug disposition and action ('pharmacogenes') can affect drug response and toxicity, especially when in tissues of pharmacological importance. Previous studies have relied primarily on microarrays to understand gene expression differences, or have focused on a single tissue or small number of samples. The goal of this study was to use RNA-sequencing (RNA-seq) to determine the expression levels and alternative splicing of 389 Pharmacogenomics Research Network pharmacogenes across four tissues (liver, kidney, heart and adipose) and lymphoblastoid cell lines, which are used widely in pharmacogenomics studies. Analysis of RNA-seq data from 139 different individuals across the 5 tissues (20-45 individuals per tissue type) revealed substantial variation in both expression levels and splicing across samples and tissue types. Comparison with GTEx data yielded a consistent picture. This in-depth exploration also revealed 183 splicing events in pharmacogenes that were previously not annotated. Overall, this study serves as a rich resource for the research community to inform biomarker and drug discovery and use.
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16 MeSH Terms
Identification of a Novel Transcript and Regulatory Mechanism for Microsomal Triglyceride Transfer Protein.
Suzuki T, Brown JJ, Swift LL
(2016) PLoS One 11: e0147252
MeSH Terms: Alternative Splicing, Animals, CHO Cells, Carrier Proteins, Cricetulus, Electrophoresis, Polyacrylamide Gel, Female, HEK293 Cells, Humans, Mice, Protein Isoforms, RNA, Messenger, Rabbits, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added February 22, 2016
Microsomal triglyceride transfer protein (MTP) is essential for the assembly of triglyceride-rich apolipoprotein B-containing lipoproteins. Previous studies in our laboratory identified a novel splice variant of MTP in mice that we named MTP-B. MTP-B has a unique first exon (1B) located 2.7 kB upstream of the first exon (1A) for canonical MTP (MTP-A). The two mature isoforms, though nearly identical in sequence and function, have different tissue expression patterns. In this study we report the identification of a second MTP splice variant (MTP-C), which contains both exons 1B and 1A. MTP-C is expressed in all the tissues we tested. In cells transfected with MTP-C, protein expression was less than 15% of that found when the cells were transfected with MTP-A or MTP-B. In silico analysis of the 5'-UTR of MTP-C revealed seven ATGs upstream of the start site for MTP-A, which is the only viable start site in frame with the main coding sequence. One of those ATGs was located in the 5'-UTR for MTP-A. We generated reporter constructs in which the 5'-UTRs of MTP-A or MTP-C were inserted between an SV40 promoter and the coding sequence of the luciferase gene and transfected these constructs into HEK 293 cells. Luciferase activity was significantly reduced by the MTP-C 5'-UTR, but not by the MTP-A 5'-UTR. We conclude that alternative splicing plays a key role in regulating MTP expression by introducing unique 5'-UTRs, which contain elements that alter translation efficiency, enabling the cell to optimize MTP levels and activity.
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14 MeSH Terms
Urinary oncofetal ED-A fibronectin correlates with poor prognosis in patients with bladder cancer.
Arnold SA, Loomans HA, Ketova T, Andl CD, Clark PE, Zijlstra A
(2016) Clin Exp Metastasis 33: 29-44
MeSH Terms: Adult, Aged, Aged, 80 and over, Alternative Splicing, Area Under Curve, Biomarkers, Tumor, Blotting, Western, Carcinoma, Transitional Cell, Enzyme-Linked Immunosorbent Assay, Female, Fibronectins, Fluorescent Antibody Technique, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Prognosis, Protein Isoforms, ROC Curve, Sensitivity and Specificity, Urinary Bladder Neoplasms
Show Abstract · Added October 13, 2015
The extracellular matrix protein fibronectin (FN) contributes to the structural integrity of tissues as well as the adhesive and migratory functions of cells. While FN is abundantly expressed in adult tissues, the expression of several alternatively spliced FN isoforms is restricted to embryonic development, tissue remodeling and cancer. These FN isoforms, designated ED-A and ED-B, are frequently expressed by cancer cells, tumor-associated fibroblasts and newly forming blood vessels. Using a highly sensitive collagen-based indirect ELISA, we evaluated the correlation of urinary ED-A and ED-B at time of cystectomy with overall survival in patients with high-grade bladder cancer (BCa). Detectable levels of total FN as well as ED-A and ED-B were found in urine from 85, 73 and 51 % of BCa patients, respectively. The presence of urinary ED-A was a significant independent predictor of 2-year overall survival (OS) after adjusting for age, tumor stage, lymph node stage, and urinary creatinine by multivariable Logistic Regression (p = 0.029, OR = 4.26, 95 % CI 1.16-15.71) and improved accuracy by 3.6 %. Furthermore, detection of ED-A in the urine was a significant discriminator of survival specifically in BCa patients with negative lymph node status (Log-Rank, p = 0.006; HR = 5.78, 95 % CI 1.39-24.13). Lastly, multivariable Cox proportional hazards analysis revealed that urinary ED-A was an independent prognostic indicator of 5-year OS rate for patients with BCa (p = 0.04, HR = 2.20, 95 % CI 1.04-4.69). Together, these data suggest that cancer-derived, alternatively spliced FN isoforms can act as prognostic indicators and that additional studies are warranted to assess the clinical utility of ED-A in BCa.
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21 MeSH Terms
Revealing Missing Human Protein Isoforms Based on Ab Initio Prediction, RNA-seq and Proteomics.
Hu Z, Scott HS, Qin G, Zheng G, Chu X, Xie L, Adelson DL, Oftedal BE, Venugopal P, Babic M, Hahn CN, Zhang B, Wang X, Li N, Wei C
(2015) Sci Rep 5: 10940
MeSH Terms: Algorithms, Alternative Splicing, Computational Biology, Datasets as Topic, Humans, Open Reading Frames, Protein Isoforms, Proteomics, Reproducibility of Results, Sequence Analysis, RNA, Transcription, Genetic
Show Abstract · Added February 15, 2016
Biological and biomedical research relies on comprehensive understanding of protein-coding transcripts. However, the total number of human proteins is still unknown due to the prevalence of alternative splicing. In this paper, we detected 31,566 novel transcripts with coding potential by filtering our ab initio predictions with 50 RNA-seq datasets from diverse tissues/cell lines. PCR followed by MiSeq sequencing showed that at least 84.1% of these predicted novel splice sites could be validated. In contrast to known transcripts, the expression of these novel transcripts were highly tissue-specific. Based on these novel transcripts, at least 36 novel proteins were detected from shotgun proteomics data of 41 breast samples. We also showed L1 retrotransposons have a more significant impact on the origin of new transcripts/genes than previously thought. Furthermore, we found that alternative splicing is extraordinarily widespread for genes involved in specific biological functions like protein binding, nucleoside binding, neuron projection, membrane organization and cell adhesion. In the end, the total number of human transcripts with protein-coding potential was estimated to be at least 204,950.
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11 MeSH Terms
Regulation of CD44E by DARPP-32-dependent activation of SRp20 splicing factor in gastric tumorigenesis.
Zhu S, Chen Z, Katsha A, Hong J, Belkhiri A, El-Rifai W
(2016) Oncogene 35: 1847-56
MeSH Terms: Alternative Splicing, Animals, Carcinogenesis, Cell Line, Tumor, Cell Proliferation, Dopamine and cAMP-Regulated Phosphoprotein 32, Gene Expression Regulation, Neoplastic, Humans, Hyaluronan Receptors, Mice, RNA-Binding Proteins, Serine-Arginine Splicing Factors, Signal Transduction, Stomach Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added September 28, 2015
CD44E is a frequently overexpressed variant of CD44 in gastric cancer. Mechanisms that regulate CD44 splicing and expression in gastric cancer remain unknown. Herein, we investigated the role of DARPP-32 (dopamine and cyclic adenosine monophosphate-regulated phosphoprotein, Mr 32000) in promoting tumor growth through regulation of CD44 splicing. Using western blot and quantitative real-time PCR analysis, our results indicated that knockdown of endogenous DARPP-32 markedly reduces the expression of CD44 V8-V10 (CD44E). Using a quantitative splicing luciferase reporter system, we detected a significant increase in the reporter activity following DARPP-32 overexpression (P<0.001). Conversely, knocking down endogenous DARPP-32 significantly attenuated the splicing activity (P<0.001). Further experiments showed that DARPP-32 regulates the expression of SRp20 splicing factor and co-exists with it in the same protein complex. Inhibition of alternative splicing with digitoxin followed by immunoprecipitation and immunoblotting indicated that DARPP-32 has an important role in regulating SRp20 protein stability. The knockdown of endogenous DARPP-32 confirmed that DARPP-32 regulates the SRp20-dependent CD44E splicing. Using tumor xenograft mouse model, knocking down endogenous DARPP-32 markedly reduced SRp20 and CD44E protein levels with a decreased tumor growth. The reconstitution of SRp20 expression in these cells rescued tumor growth. In addition, we also demonstrated frequent co-overexpression and positive correlation of DARPP-32, SRp20 and CD44E expression levels in human gastric primary tumors. Our novel findings establish for the first time the role of DARPP-32 in regulating splicing factors in gastric cancer cells. The DARPP-32-SRp20 axis has a key role in regulating the CD44E splice variant that promotes gastric tumorigenesis.
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15 MeSH Terms
Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome.
Rivas MA, Pirinen M, Conrad DF, Lek M, Tsang EK, Karczewski KJ, Maller JB, Kukurba KR, DeLuca DS, Fromer M, Ferreira PG, Smith KS, Zhang R, Zhao F, Banks E, Poplin R, Ruderfer DM, Purcell SM, Tukiainen T, Minikel EV, Stenson PD, Cooper DN, Huang KH, Sullivan TJ, Nedzel J, GTEx Consortium, Geuvadis Consortium, Bustamante CD, Li JB, Daly MJ, Guigo R, Donnelly P, Ardlie K, Sammeth M, Dermitzakis ET, McCarthy MI, Montgomery SB, Lappalainen T, MacArthur DG
(2015) Science 348: 666-9
MeSH Terms: Alternative Splicing, Gene Expression Profiling, Gene Expression Regulation, Gene Silencing, Genetic Variation, Genome, Human, Heterozygote, Humans, Nonsense Mediated mRNA Decay, Phenotype, Proteins, Transcriptome
Show Abstract · Added April 13, 2017
Accurate prediction of the functional effect of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating variants, a class of variants expected to have profound effects on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitated tissue-specific and positional effects on nonsense-mediated transcript decay and present an improved predictive model for this decay. We directly measured the effect of variants both proximal and distal to splice junctions. Furthermore, we found that robustness to heterozygous gene inactivation is not due to dosage compensation. Our results illustrate the value of transcriptome data in the functional interpretation of genetic variants.
Copyright © 2015, American Association for the Advancement of Science.
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12 MeSH Terms
Targeting of splice variants of human cytochrome P450 2C8 (CYP2C8) to mitochondria and their role in arachidonic acid metabolism and respiratory dysfunction.
Bajpai P, Srinivasan S, Ghosh J, Nagy LD, Wei S, Guengerich FP, Avadhani NG
(2014) J Biol Chem 289: 29614-30
MeSH Terms: Alternative Splicing, Amino Acid Sequence, Amino Acids, Animals, Arachidonic Acid, Aryl Hydrocarbon Hydroxylases, Biocatalysis, COS Cells, Cell Respiration, Cercopithecus aethiops, Computer Simulation, Cytochrome P-450 CYP2C8, Heme, Hep G2 Cells, Humans, Isoenzymes, Microsomes, Liver, Mitochondria, Models, Molecular, Molecular Sequence Data, Oxidation-Reduction, Oxidative Stress, Protein Binding, Protein Transport, RNA, Messenger, Reactive Oxygen Species, Sequence Alignment
Show Abstract · Added January 20, 2015
In this study, we found that the full-length CYP2C8 (WT CYP2C8) and N-terminal truncated splice variant 3 (∼ 44-kDa mass) are localized in mitochondria in addition to the endoplasmic reticulum. Analysis of human livers showed that the mitochondrial levels of these two forms varied markedly. Molecular modeling based on the x-ray crystal structure coordinates of CYP2D6 and CYP2C8 showed that despite lacking the N-terminal 102 residues variant 3 possessed nearly complete substrate binding and heme binding pockets. Stable expression of cDNAs in HepG2 cells showed that the WT protein is mostly targeted to the endoplasmic reticulum and at low levels to mitochondria, whereas variant 3 is primarily targeted to mitochondria and at low levels to the endoplasmic reticulum. Enzyme reconstitution experiments showed that both microsomal and mitochondrial WT CYP2C8 efficiently catalyzed paclitaxel 6-hydroxylation. However, mitochondrial variant 3 was unable to catalyze this reaction possibly because of its inability to stabilize the large 854-Da substrate. Conversely, mitochondrial variant 3 catalyzed the metabolism of arachidonic acid into 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids and 20-hydroxyeicosatetraenoic acid when reconstituted with adrenodoxin and adrenodoxin reductase. HepG2 cells stably expressing variant 3 generated higher levels of reactive oxygen species and showed a higher level of mitochondrial respiratory dysfunction. This study suggests that mitochondrially targeted variant 3 CYP2C8 may contribute to oxidative stress in various tissues.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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27 MeSH Terms
Insm1 promotes endocrine cell differentiation by modulating the expression of a network of genes that includes Neurog3 and Ripply3.
Osipovich AB, Long Q, Manduchi E, Gangula R, Hipkens SB, Schneider J, Okubo T, Stoeckert CJ, Takada S, Magnuson MA
(2014) Development 141: 2939-49
MeSH Terms: Alleles, Alternative Splicing, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Lineage, Cell Movement, Cell Proliferation, Cell Separation, DNA-Binding Proteins, Endocrine Cells, Extracellular Matrix, Flow Cytometry, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Genes, Reporter, Green Fluorescent Proteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Pancreas, RNA, RNA Splicing, Repressor Proteins, Stem Cells, Time Factors, Transcription Factors, Transcription, Genetic
Show Abstract · Added July 26, 2014
Insulinoma associated 1 (Insm1) plays an important role in regulating the development of cells in the central and peripheral nervous systems, olfactory epithelium and endocrine pancreas. To better define the role of Insm1 in pancreatic endocrine cell development we generated mice with an Insm1(GFPCre) reporter allele and used them to study Insm1-expressing and null populations. Endocrine progenitor cells lacking Insm1 were less differentiated and exhibited broad defects in hormone production, cell proliferation and cell migration. Embryos lacking Insm1 contained greater amounts of a non-coding Neurog3 mRNA splice variant and had fewer Neurog3/Insm1 co-expressing progenitor cells, suggesting that Insm1 positively regulates Neurog3. Moreover, endocrine progenitor cells that express either high or low levels of Pdx1, and thus may be biased towards the formation of specific cell lineages, exhibited cell type-specific differences in the genes regulated by Insm1. Analysis of the function of Ripply3, an Insm1-regulated gene enriched in the Pdx1-high cell population, revealed that it negatively regulates the proliferation of early endocrine cells. Taken together, these findings indicate that in developing pancreatic endocrine cells Insm1 promotes the transition from a ductal progenitor to a committed endocrine cell by repressing a progenitor cell program and activating genes essential for RNA splicing, cell migration, controlled cellular proliferation, vasculogenesis, extracellular matrix and hormone secretion.
© 2014. Published by The Company of Biologists Ltd.
3 Communities
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28 MeSH Terms
TRIP8b is required for maximal expression of HCN1 in the mouse retina.
Pan Y, Bhattarai S, Modestou M, Drack AV, Chetkovich DM, Baker SA
(2014) PLoS One 9: e85850
MeSH Terms: Alternative Splicing, Animals, Cell Membrane, Flicker Fusion, Gene Expression Regulation, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Membrane Proteins, Mice, Mice, Knockout, Peroxins, Photoreceptor Cells, Protein Binding, Protein Isoforms, Protein Transport, Retina
Show Abstract · Added April 2, 2019
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are cation-selective channels present in retina, brain and heart. The activity of HCN channels contributes to signal integration, cell excitability and pacemaker activity. HCN1 channels expressed in photoreceptors participate in keeping light responses transient and are required for normal mesopic vision. The subcellular localization of HCN1 varies among cell types. In photoreceptors HCN1 is concentrated in the inner segments while in other retinal neurons, HCN1 is evenly distributed though the cell. This is in contrast to hippocampal neurons where HCN1 is concentrated in a subset of dendrites. A key regulator of HCN1 trafficking and activity is tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b). Multiple splice isoforms of TRIP8b are expressed throughout the brain and can differentially regulate the surface expression and activity of HCN1. The purpose of the present study was to determine which isoforms of TRIP8b are expressed in the retina and to test if loss of TRIP8b alters HCN1 expression or trafficking. We found that TRIP8b colocalizes with HCN1 in multiple retina neurons and all major splice isoforms of TRIP8b are expressed in the retina. Photoreceptors express three different isoforms. In TRIP8b knockout mice, the ability of HCN1 to traffic to the surface of retinal neurons is unaffected. However, there is a large decrease in the total amount of HCN1. We conclude that TRIP8b in the retina is needed to achieve maximal expression of HCN1.
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MeSH Terms
Genomics of alternative splicing: evolution, development and pathophysiology.
Gamazon ER, Stranger BE
(2014) Hum Genet 133: 679-87
MeSH Terms: Alternative Splicing, Biological Evolution, Databases, Genetic, Genetic Therapy, Genetic Variation, Genome, Human, Genomics, Humans, Muscular Dystrophy, Duchenne, Myelodysplastic Syndromes, Oligonucleotides, Antisense, Software, Transcriptome, beta-Thalassemia
Show Abstract · Added April 13, 2017
Alternative splicing is a major cellular mechanism in metazoans for generating proteomic diversity. A large proportion of protein-coding genes in multicellular organisms undergo alternative splicing, and in humans, it has been estimated that nearly 90 % of protein-coding genes-much larger than expected-are subject to alternative splicing. Genomic analyses of alternative splicing have illuminated its universal role in shaping the evolution of genomes, in the control of developmental processes, and in the dynamic regulation of the transcriptome to influence phenotype. Disruption of the splicing machinery has been found to drive pathophysiology, and indeed reprogramming of aberrant splicing can provide novel approaches to the development of molecular therapy. This review focuses on the recent progress in our understanding of alternative splicing brought about by the unprecedented explosive growth of genomic data and highlights the relevance of human splicing variation on disease and therapy.
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14 MeSH Terms