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RNAseq by Total RNA Library Identifies Additional RNAs Compared to Poly(A) RNA Library.
Guo Y, Zhao S, Sheng Q, Guo M, Lehmann B, Pietenpol J, Samuels DC, Shyr Y
(2015) Biomed Res Int 2015: 862130
MeSH Terms: Gene Expression Profiling, Gene Library, Humans, Open Reading Frames, Poly A, RNA, RNA, Ribosomal, Sequence Analysis, RNA
Show Abstract · Added February 15, 2016
The most popular RNA library used for RNA sequencing is the poly(A) captured RNA library. This library captures RNA based on the presence of poly(A) tails at the 3' end. Another type of RNA library for RNA sequencing is the total RNA library which differs from the poly(A) library by capture method and price. The total RNA library costs more and its capture of RNA is not dependent on the presence of poly(A) tails. In practice, only ribosomal RNAs and small RNAs are washed out in the total RNA library preparation. To evaluate the ability of detecting RNA for both RNA libraries we designed a study using RNA sequencing data of the same two breast cancer cell lines from both RNA libraries. We found that the RNA expression values captured by both RNA libraries were highly correlated. However, the number of RNAs captured was significantly higher for the total RNA library. Furthermore, we identify several subsets of protein coding RNAs that were not captured efficiently by the poly(A) library. One of the most noticeable is the histone-encode genes, which lack the poly(A) tail.
1 Communities
3 Members
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8 MeSH Terms
Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily.
McCulloch KM, McCranie EK, Smith JA, Sarwar M, Mathieu JL, Gitschlag BL, Du Y, Bachmann BO, Iverson TM
(2015) Proc Natl Acad Sci U S A 112: 11547-52
MeSH Terms: Aminoglycosides, Anti-Bacterial Agents, Catalytic Domain, Crystallography, X-Ray, Cyclization, Hydrogen, Hygromycin B, Metals, Micromonospora, Multigene Family, Oligosaccharides, Open Reading Frames, Oxidation-Reduction, Oxygen, Oxygenases, Phylogeny, Protein Binding, Protein Structure, Secondary, Reproducibility of Results, Streptomyces
Show Abstract · Added April 1, 2019
Orthosomycins are oligosaccharide antibiotics that include avilamycin, everninomicin, and hygromycin B and are hallmarked by a rigidifying interglycosidic spirocyclic ortho-δ-lactone (orthoester) linkage between at least one pair of carbohydrates. A subset of orthosomycins additionally contain a carbohydrate capped by a methylenedioxy bridge. The orthoester linkage is necessary for antibiotic activity but rarely observed in natural products. Orthoester linkage and methylenedioxy bridge biosynthesis require similar oxidative cyclizations adjacent to a sugar ring. We have identified a conserved group of nonheme iron, α-ketoglutarate-dependent oxygenases likely responsible for this chemistry. High-resolution crystal structures of the EvdO1 and EvdO2 oxygenases of everninomicin biosynthesis, the AviO1 oxygenase of avilamycin biosynthesis, and HygX of hygromycin B biosynthesis show how these enzymes accommodate large substrates, a challenge that requires a variation in metal coordination in HygX. Excitingly, the ternary complex of HygX with cosubstrate α-ketoglutarate and putative product hygromycin B identified an orientation of one glycosidic linkage of hygromycin B consistent with metal-catalyzed hydrogen atom abstraction from substrate. These structural results are complemented by gene disruption of the oxygenases evdO1 and evdMO1 from the everninomicin biosynthetic cluster, which demonstrate that functional oxygenase activity is critical for antibiotic production. Our data therefore support a role for these enzymes in the production of key features of the orthosomycin antibiotics.
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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
Upstream open reading frame in 5'-untranslated region reduces titin mRNA translational efficiency.
Cadar AG, Zhong L, Lin A, Valenzuela MO, Lim CC
(2014) Biochem Biophys Res Commun 453: 185-91
MeSH Terms: 5' Untranslated Regions, Animals, Base Sequence, Cell Line, Connectin, Doxorubicin, Gene Expression Regulation, HEK293 Cells, Half-Life, Humans, Mice, Molecular Sequence Data, Myocytes, Cardiac, Open Reading Frames, Polymorphism, Single Nucleotide, Protein Kinases, RNA Stability, RNA, Messenger, Rats, Sarcomeres, Sequence Homology, Nucleic Acid
Show Abstract · Added February 19, 2015
Titin is the largest known protein and a critical determinant of myofibril elasticity and sarcomere structure in striated muscle. Accumulating evidence that mRNA transcripts are post-transcriptionally regulated by specific motifs located in the flanking untranslated regions (UTRs) led us to consider the role of titin 5'-UTR in regulating its translational efficiency. Titin 5'-UTR is highly homologous between human, mouse, and rat, and sequence analysis revealed the presence of a stem-loop and two upstream AUG codons (uAUGs) converging on a shared in frame stop codon. We generated a mouse titin 5'-UTR luciferase reporter construct and targeted the stem-loop and each uAUG for mutation. The wild-type and mutated constructs were transfected into the cardiac HL-1 cell line and primary neonatal rat ventricular myocytes (NRVM). SV40 driven 5'-UTR luciferase activity was significantly suppressed by wild-type titin 5'-UTR (∼ 70% in HL-1 cells and ∼ 60% in NRVM). Mutating both uAUGs was found to alleviate titin 5'-UTR suppression, while eliminating the stem-loop had no effect. Treatment with various growth stimuli: pacing, PMA or neuregulin had no effect on titin 5'-UTR luciferase activity. Doxorubicin stress stimuli reduced titin 5'-UTR suppression, while H2O2 had no effect. A reported single nucleotide polymorphism (SNP) rs13422986 at position -4 of the uAUG2 was introduced and found to further repress titin 5'-UTR luciferase activity. We conclude that the uAUG motifs in titin 5'-UTR serve as translational repressors in the control of titin gene expression, and that mutations/SNPs of the uAUGs or doxorubicin stress could alter titin translational efficiency.
Copyright © 2014 Elsevier Inc. All rights reserved.
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21 MeSH Terms
An expressed retrogene of the master embryonic stem cell gene POU5F1 is associated with prostate cancer susceptibility.
Breyer JP, Dorset DC, Clark TA, Bradley KM, Wahlfors TA, McReynolds KM, Maynard WH, Chang SS, Cookson MS, Smith JA, Schleutker J, Dupont WD, Smith JR
(2014) Am J Hum Genet 94: 395-404
MeSH Terms: Adolescent, Adult, Aged, Alleles, Case-Control Studies, Cell Nucleus, Cell Transformation, Neoplastic, Databases, Genetic, Embryonic Stem Cells, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genetic Variation, Genotype, Haplotypes, Humans, Male, Middle Aged, Mutation, Missense, Octamer Transcription Factor-3, Open Reading Frames, Prostatic Neoplasms, Quantitative Trait Loci, Risk, Sequence Analysis, DNA, Transcription, Genetic, Young Adult
Show Abstract · Added March 20, 2014
Genetic association studies of prostate and other cancers have identified a major risk locus at chromosome 8q24. Several independent risk variants at this locus alter transcriptional regulatory elements, but an affected gene and mechanism for cancer predisposition have remained elusive. The retrogene POU5F1B within the locus has a preserved open reading frame encoding a homolog of the master embryonic stem cell transcription factor Oct4. We find that 8q24 risk alleles are expression quantitative trait loci correlated with reduced expression of POU5F1B in prostate tissue and that predicted deleterious POU5F1B missense variants are also associated with risk of transformation. POU5F1 is known to be self-regulated by the encoded Oct4 transcription factor. We further observe that POU5F1 expression is directly correlated with POU5F1B expression. Our results suggest that a pathway critical to self-renewal of embryonic stem cells may also have a role in the origin of cancer.
Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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26 MeSH Terms
Use of a promiscuous, constitutively-active bacterial enhancer-binding protein to define the σ⁵⁴ (RpoN) regulon of Salmonella Typhimurium LT2.
Samuels DJ, Frye JG, Porwollik S, McClelland M, Mrázek J, Hoover TR, Karls AC
(2013) BMC Genomics 14: 602
MeSH Terms: Binding Sites, Chromatin Immunoprecipitation, DNA-Binding Proteins, Gene Expression Regulation, Bacterial, Oligonucleotide Array Sequence Analysis, Open Reading Frames, Operon, Promoter Regions, Genetic, RNA Polymerase Sigma 54, Regulon, Salmonella typhimurium, Transcriptional Activation
Show Abstract · Added December 12, 2013
BACKGROUND - Sigma54, or RpoN, is an alternative σ factor found widely in eubacteria. A significant complication in analysis of the global σ⁵⁴ regulon in a bacterium is that the σ⁵⁴ RNA polymerase holoenzyme requires interaction with an active bacterial enhancer-binding protein (bEBP) to initiate transcription at a σ⁵⁴-dependent promoter. Many bacteria possess multiple bEBPs, which are activated by diverse environmental stimuli. In this work, we assess the ability of a promiscuous, constitutively-active bEBP-the AAA+ ATPase domain of DctD from Sinorhizobium meliloti-to activate transcription from all σ⁵⁴-dependent promoters for the characterization of the σ⁵⁴ regulon of Salmonella Typhimurium LT2.
RESULTS - The AAA+ ATPase domain of DctD was able to drive transcription from nearly all previously characterized or predicted σ⁵⁴-dependent promoters in Salmonella under a single condition. These promoters are controlled by a variety of native activators and, under the condition tested, are not transcribed in the absence of the DctD AAA+ ATPase domain. We also identified a novel σ⁵⁴-dependent promoter upstream of STM2939, a homolog of the cas1 component of a CRISPR system. ChIP-chip analysis revealed at least 70 σ⁵⁴ binding sites in the chromosome, of which 58% are located within coding sequences. Promoter-lacZ fusions with selected intragenic σ⁵⁴ binding sites suggest that many of these sites are capable of functioning as σ⁵⁴-dependent promoters.
CONCLUSION - Since the DctD AAA + ATPase domain proved effective in activating transcription from the diverse σ⁵⁴-dependent promoters of the S. Typhimurium LT2 σ⁵⁴ regulon under a single growth condition, this approach is likely to be valuable for examining σ⁵⁴ regulons in other bacterial species. The S. Typhimurium σ⁵⁴ regulon included a high number of intragenic σ⁵⁴ binding sites/promoters, suggesting that σ⁵⁴ may have multiple regulatory roles beyond the initiation of transcription at the start of an operon.
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12 MeSH Terms
Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.
Sen P, Yang Y, Navarro C, Silva I, Szafranski P, Kolodziejska KE, Dharmadhikari AV, Mostafa H, Kozakewich H, Kearney D, Cahill JB, Whitt M, Bilic M, Margraf L, Charles A, Goldblatt J, Gibson K, Lantz PE, Garvin AJ, Petty J, Kiblawi Z, Zuppan C, McConkie-Rosell A, McDonald MT, Peterson-Carmichael SL, Gaede JT, Shivanna B, Schady D, Friedlich PS, Hays SR, Palafoll IV, Siebers-Renelt U, Bohring A, Finn LS, Siebert JR, Galambos C, Nguyen L, Riley M, Chassaing N, Vigouroux A, Rocha G, Fernandes S, Brumbaugh J, Roberts K, Ho-Ming L, Lo IF, Lam S, Gerychova R, Jezova M, Valaskova I, Fellmann F, Afshar K, Giannoni E, Muhlethaler V, Liang J, Beckmann JS, Lioy J, Deshmukh H, Srinivasan L, Swarr DT, Sloman M, Shaw-Smith C, van Loon RL, Hagman C, Sznajer Y, Barrea C, Galant C, Detaille T, Wambach JA, Cole FS, Hamvas A, Prince LS, Diderich KE, Brooks AS, Verdijk RM, Ravindranathan H, Sugo E, Mowat D, Baker ML, Langston C, Welty S, Stankiewicz P
(2013) Hum Mutat 34: 801-11
MeSH Terms: Amino Acid Sequence, Chromosome Mapping, Databases, Genetic, Female, Forkhead Transcription Factors, Gene Dosage, Gene Order, Humans, Infant, Infant, Newborn, Male, Molecular Sequence Data, Mutation, Open Reading Frames, Persistent Fetal Circulation Syndrome, Protein Interaction Domains and Motifs, Sequence Alignment
Show Abstract · Added January 20, 2015
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.
© 2013 Wiley Periodicals, Inc.
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17 MeSH Terms
Evolution and taxonomic classification of human papillomavirus 16 (HPV16)-related variant genomes: HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67.
Chen Z, Schiffman M, Herrero R, Desalle R, Anastos K, Segondy M, Sahasrabuddhe VV, Gravitt PE, Hsing AW, Burk RD
(2011) PLoS One 6: e20183
MeSH Terms: Algorithms, Alphapapillomavirus, Bayes Theorem, Biological Evolution, Female, Genetic Variation, Genome, Human papillomavirus 16, Humans, Open Reading Frames, Phylogeny, Polymorphism, Single Nucleotide, Uterine Cervical Neoplasms
Show Abstract · Added March 5, 2014
BACKGROUND - Human papillomavirus 16 (HPV16) species group (alpha-9) of the Alphapapillomavirus genus contains HPV16, HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67. These HPVs account for 75% of invasive cervical cancers worldwide. Viral variants of these HPVs differ in evolutionary history and pathogenicity. Moreover, a comprehensive nomenclature system for HPV variants is lacking, limiting comparisons between studies.
METHODS - DNA from cervical samples previously characterized for HPV type were obtained from multiple geographic regions to screen for novel variants. The complete 8 kb genomes of 120 variants representing the major and minor lineages of the HPV16-related alpha-9 HPV types were sequenced to capture maximum viral heterogeneity. Viral evolution was characterized by constructing phylogenic trees based on complete genomes using multiple algorithms. Maximal and viral region specific divergence was calculated by global and pairwise alignments. Variant lineages were classified and named using an alphanumeric system; the prototype genome was assigned to the A lineage for all types.
RESULTS - The range of genome-genome sequence heterogeneity varied from 0.6% for HPV35 to 2.2% for HPV52 and included 1.4% for HPV31, 1.1% for HPV33, 1.7% for HPV58 and 1.1% for HPV67. Nucleotide differences of approximately 1.0% - 10.0% and 0.5%-1.0% of the complete genomes were used to define variant lineages and sublineages, respectively. Each gene/region differs in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) /noncoding region 2 (NCR2) >upstream regulatory region (URR)> E6/E7 > E2/L2 > E1/L1.
CONCLUSIONS - These data define maximum viral genomic heterogeneity of HPV16-related alpha-9 HPV variants. The proposed nomenclature system facilitates the comparison of variants across epidemiological studies. Sequence diversity and phylogenies of this clinically important group of HPVs provides the basis for further studies of discrete viral evolution, epidemiology, pathogenesis and preventative/therapeutic interventions.
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13 MeSH Terms
Genome-wide transcriptional dependence on conserved regions of Mot1.
Venters BJ, Irvin JD, Gramlich P, Pugh BF
(2011) Mol Cell Biol 31: 2253-61
MeSH Terms: Adenosine Triphosphatases, Chromatin Immunoprecipitation, Conserved Sequence, DNA-Binding Proteins, Gene Expression Regulation, Fungal, Genome, Fungal, Microarray Analysis, Mutation, Open Reading Frames, Promoter Regions, Genetic, Protein Structure, Tertiary, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Deletion, TATA-Binding Protein Associated Factors, TATA-Box Binding Protein
Show Abstract · Added March 5, 2014
TATA binding protein (TBP) plays a central role in transcription complex assembly and is regulated by a variety of transcription factors, including Mot1. Mot1 is an essential protein in Saccharomyces cerevisiae that exerts both negative and positive effects on transcription via interactions with TBP. It contains two conserved regions important for TBP interactions, another conserved region that hydrolyzes ATP to remove TBP from DNA, and a fourth conserved region with unknown function. Whether these regions contribute equally to transcriptional regulation genome-wide is unknown. Here, we employ a transient-replacement assay using deletion derivatives in the conserved regions of Mot1 to investigate their contributions to gene regulation throughout the S. cerevisiae genome. These four regions of Mot1 are essential for growth and are generally required for all Mot1-regulated genes. Loss of the ATPase region, but not other conserved regions, caused TBP to redistribute away from a subset of Mot1-inhibited genes, leading to decreased expression of those genes. A corresponding increase in TBP occupancy and expression occurred at another set of genes that are normally Mot1 independent. The data suggest that Mot1 uses ATP hydrolysis to redistribute accessible TBP away from intrinsically preferred sites to other sites of intrinsically low preference.
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16 MeSH Terms
Control of copper resistance and inorganic sulfur metabolism by paralogous regulators in Staphylococcus aureus.
Grossoehme N, Kehl-Fie TE, Ma Z, Adams KW, Cowart DM, Scott RA, Skaar EP, Giedroc DP
(2011) J Biol Chem 286: 13522-31
MeSH Terms: Bacterial Proteins, Copper, Drug Resistance, Bacterial, Open Reading Frames, Operon, Repressor Proteins, Staphylococcus aureus, Sulfur
Show Abstract · Added February 11, 2016
All strains of Staphylococcus aureus encode a putative copper-sensitive operon repressor (CsoR) and one other CsoR-like protein of unknown function. We show here that NWMN_1991 encodes a bona fide Cu(I)-inducible CsoR of a genetically unlinked copA-copZ copper resistance operon in S. aureus strain Newman. In contrast, an unannotated open reading frame found between NWMN_0027 and NWMN_0026 (denoted NWMN_0026.5) encodes a CsoR-like regulator that represses expression of adjacent genes by binding specifically to a pair of canonical operator sites positioned in the NWMN_0027-0026.5 intergenic region. Inspection of these regulated genes suggests a role in assimilation of inorganic sulfur from thiosulfate and vectorial sulfur transfer, and we designate NWMN_0026.5 as CstR (CsoR-like sulfur transferase repressor). Expression analysis demonstrates that CsoR and CstR control their respective regulons in response to distinct stimuli with no overlap in vivo. Unlike CsoR, CstR does not form a stable complex with Cu(I); operator binding is instead inhibited by oxidation of the intersubunit cysteine pair to a mixture of disulfide and trisulfide linkages by a likely metabolite of thiosulfate assimilation, sulfite. CsoR is unreactive toward sulfite under the same conditions. We conclude that CsoR and CstR are paralogs in S. aureus that function in the same cytoplasm to control distinct physiological processes.
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8 MeSH Terms