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Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage.
Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR
(2017) Nature 551: 464-471
MeSH Terms: Adenosine Deaminase, Base Pairing, CRISPR-Associated Proteins, Cell Line, Tumor, DNA, DNA Cleavage, Gene Editing, Genome, Human, HEK293 Cells, Humans, Models, Molecular, Polymorphism, Single Nucleotide
Show Abstract · Added March 13, 2018
The spontaneous deamination of cytosine is a major source of transitions from C•G to T•A base pairs, which account for half of known pathogenic point mutations in humans. The ability to efficiently convert targeted A•T base pairs to G•C could therefore advance the study and treatment of genetic diseases. The deamination of adenine yields inosine, which is treated as guanine by polymerases, but no enzymes are known to deaminate adenine in DNA. Here we describe adenine base editors (ABEs) that mediate the conversion of A•T to G•C in genomic DNA. We evolved a transfer RNA adenosine deaminase to operate on DNA when fused to a catalytically impaired CRISPR-Cas9 mutant. Extensive directed evolution and protein engineering resulted in seventh-generation ABEs that convert targeted A•T base pairs efficiently to G•C (approximately 50% efficiency in human cells) with high product purity (typically at least 99.9%) and low rates of indels (typically no more than 0.1%). ABEs introduce point mutations more efficiently and cleanly, and with less off-target genome modification, than a current Cas9 nuclease-based method, and can install disease-correcting or disease-suppressing mutations in human cells. Together with previous base editors, ABEs enable the direct, programmable introduction of all four transition mutations without double-stranded DNA cleavage.
0 Communities
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1 Resources
12 MeSH Terms
Dynamic landscape and regulation of RNA editing in mammals.
Tan MH, Li Q, Shanmugam R, Piskol R, Kohler J, Young AN, Liu KI, Zhang R, Ramaswami G, Ariyoshi K, Gupte A, Keegan LP, George CX, Ramu A, Huang N, Pollina EA, Leeman DS, Rustighi A, Goh YPS, GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, NIH/NCI, NIH/NHGRI, NIH/NIMH, NIH/NIDA, Biospecimen Collection Source Site—NDRI, Biospecimen Collection Source Site—RPCI, Biospecimen Core Resource—VARI, Brain Bank Repository—University of Miami Brain Endowment Bank, Leidos Biomedical—Project Management, ELSI Study, Genome Browser Data Integration &Visualization—EBI, Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz, Chawla A, Del Sal G, Peltz G, Brunet A, Conrad DF, Samuel CE, O'Connell MA, Walkley CR, Nishikura K, Li JB
(2017) Nature 550: 249-254
MeSH Terms: Adenosine Deaminase, Animals, Female, Genotype, HEK293 Cells, Humans, Male, Mice, Muscles, Nuclear Proteins, Organ Specificity, Primates, Proteolysis, RNA Editing, RNA-Binding Proteins, Spatio-Temporal Analysis, Species Specificity, Transcriptome
Show Abstract · Added October 27, 2017
Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules. Although many editing sites have recently been discovered, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.
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18 MeSH Terms
Reovirus-mediated induction of ADAR1 (p150) minimally alters RNA editing patterns in discrete brain regions.
Hood JL, Morabito MV, Martinez CR, Gilbert JA, Ferrick EA, Ayers GD, Chappell JD, Dermody TS, Emeson RB
(2014) Mol Cell Neurosci 61: 97-109
MeSH Terms: Adenosine Deaminase, Age Factors, Analysis of Variance, Animals, Animals, Newborn, Body Weight, Brain, Gene Expression Regulation, Viral, Mice, Mice, Inbred C57BL, Protein Isoforms, RNA Editing, RNA, Messenger, RNA-Binding Proteins, Reoviridae
Show Abstract · Added January 20, 2015
Transcripts encoding ADAR1, a double-stranded, RNA-specific adenosine deaminase involved in the adenosine-to-inosine (A-to-I) editing of mammalian RNAs, can be alternatively spliced to produce an interferon-inducible protein isoform (p150) that is up-regulated in both cell culture and in vivo model systems in response to pathogen or interferon stimulation. In contrast to other tissues, p150 is expressed at extremely low levels in the brain and it is unclear what role, if any, this isoform may play in the innate immune response of the central nervous system (CNS) or whether the extent of editing for RNA substrates critical for CNS function is affected by its induction. To investigate the expression of ADAR1 isoforms in response to viral infection and subsequent alterations in A-to-I editing profiles for endogenous ADAR targets, we used a neurotropic strain of reovirus to infect neonatal mice and quantify A-to-I editing in discrete brain regions using a multiplexed, high-throughput sequencing strategy. While intracranial injection of reovirus resulted in a widespread increase in the expression of ADAR1 (p150) in multiple brain regions and peripheral organs, significant changes in site-specific A-to-I conversion were quite limited, suggesting that steady-state levels of p150 expression are not a primary determinant for modulating the extent of editing for numerous ADAR targets in vivo.
Copyright © 2014 Elsevier Inc. All rights reserved.
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15 MeSH Terms
ADAR1 is essential for intestinal homeostasis and stem cell maintenance.
Qiu W, Wang X, Buchanan M, He K, Sharma R, Zhang L, Wang Q, Yu J
(2013) Cell Death Dis 4: e599
MeSH Terms: Adenosine Deaminase, Animals, Antineoplastic Agents, Hormonal, Apoptosis, Cell Differentiation, Cells, Cultured, Endoplasmic Reticulum Stress, Inflammation, Interferons, Intestinal Mucosa, Intestines, Mice, Mice, Knockout, RNA-Binding Proteins, Receptors, G-Protein-Coupled, Signal Transduction, Stem Cells, Tamoxifen, Wnt Proteins
Show Abstract · Added July 28, 2015
Adenosine deaminase acting on RNA 1 (ADAR1) is a double-stranded RNA-editing enzyme that converts adenosine (A) to inosine (I), and essential for normal development. In this study, we reported an essential role of ADAR1 in the survival and maintenance of intestinal stem cells and intestinal homoeostasis by suppressing endoplasmic reticulum (ER) stress and interferon (IFN) signaling. ADAR1 was highly expressed in the Lgr5+ cells, and its deletion in adult mice led to a rapid apoptosis and loss of these actively cycling stem cells in the small intestine and colon. ADAR1 deletion resulted in a drastic expansion of progenitors and Paneth cells but a reduction of three other major epithelial lineages. Moreover, loss of ADAR1 induced ER stress and activation of IFN signaling, and altered expression in WNT targets, followed by intestinal inflammation. An ER stress inhibitor partially suppressed crypt apoptosis. Finally, data from cultured intestinal crypts demonstrated that loss of ADAR1 in the epithelial cells is the primary cause of these effects. These results support an essential role of ADAR1 and RNA editing in tissue homeostasis and stem cells.
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19 MeSH Terms
Role of A2B adenosine receptors in regulation of paracrine functions of stem cell antigen 1-positive cardiac stromal cells.
Ryzhov S, Goldstein AE, Novitskiy SV, Blackburn MR, Biaggioni I, Feoktistov I
(2012) J Pharmacol Exp Ther 341: 764-74
MeSH Terms: Adenosine, Adenosine Deaminase, Agammaglobulinemia, Animals, Antigens, Ly, Cells, Cultured, Chemokine CXCL1, Female, Interleukin-6, Male, Membrane Proteins, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myocardial Infarction, Myocardium, Paracrine Communication, Platelet Endothelial Cell Adhesion Molecule-1, RNA, Messenger, Receptor, Adenosine A2B, Severe Combined Immunodeficiency, Stem Cells, Up-Regulation, Vascular Endothelial Growth Factor A
Show Abstract · Added May 29, 2014
The existence of multipotent cardiac stromal cells expressing stem cell antigen (Sca)-1 has been reported, and their proangiogenic properties have been demonstrated in myocardial infarction models. In this study, we tested the hypothesis that stimulation of adenosine receptors on cardiac Sca-1(+) cells up-regulates their secretion of proangiogenic factors. We found that Sca-1 is expressed in subsets of mouse cardiac stromal CD31(-) and endothelial CD31(+) cells. The population of Sca-1(+)CD31(+) endothelial cells was significantly reduced, whereas the population of Sca-1(+)CD31(-) stromal cells was increased 1 week after myocardial infarction, indicating their relative functional importance in this pathophysiological process. An increase in adenosine levels in adenosine deaminase-deficient mice in vivo significantly augmented vascular endothelial growth factor (VEGF) production in cardiac Sca-1(+)CD31(-) stromal cells but not in Sca-1(+)CD31(+) endothelial cells. We found that mouse cardiac Sca-1(+)CD31(-) stromal cells predominantly express mRNA encoding A(2B) adenosine receptors. Stimulation of adenosine receptors significantly increased interleukin (IL)-6, CXCL1 (a mouse ortholog of human IL-8), and VEGF release from these cells. Using conditionally immortalized Sca-1(+)CD31(-) stromal cells obtained from wild-type and A(2B) receptor knockout mouse hearts, we demonstrated that A(2B) receptors are essential for adenosine-dependent up-regulation of their paracrine functions. We found that the human heart also harbors a population of stromal cells similar to the mouse cardiac Sca-1(+)CD31(-) stromal cells that increase release of IL-6, IL-8, and VEGF in response to A(2B) receptor stimulation. Thus, our study identified A(2B) adenosine receptors on cardiac stromal cells as potential targets for up-regulation of proangiogenic factors in the ischemic heart.
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26 MeSH Terms
Editing of neurotransmitter receptor and ion channel RNAs in the nervous system.
Hood JL, Emeson RB
(2012) Curr Top Microbiol Immunol 353: 61-90
MeSH Terms: Adenosine Deaminase, Amino Acid Sequence, Ion Channels, Molecular Sequence Data, Nervous System, RNA Editing, RNA-Binding Proteins, Receptor, Serotonin, 5-HT2C, Receptors, AMPA, Receptors, GABA-A, Receptors, Kainic Acid, Receptors, Neurotransmitter
Show Abstract · Added May 28, 2014
The central dogma of molecular biology defines the major route for the transfer of genetic information from genomic DNA to messenger RNA to three-dimensional proteins that affect structure and function. Like alternative splicing, the post-transcriptional conversion of adenosine to inosine (A-to-I) by RNA editing can dramatically expand the diversity of the transcriptome to generate multiple, functionally distinct protein isoforms from a single genomic locus. While RNA editing has been identified in virtually all tissues, such post-transcriptional modifications have been best characterized in RNAs encoding both ligand- and voltage-gated ion channels and neurotransmitter receptors. These RNA processing events have been shown to play an important role in the function of the encoded protein products and, in several cases, have been shown to be critical for the normal development and function of the nervous system.
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12 MeSH Terms
The solution structure of the ADAR2 dsRBM-RNA complex reveals a sequence-specific readout of the minor groove.
Stefl R, Oberstrass FC, Hood JL, Jourdan M, Zimmermann M, Skrisovska L, Maris C, Peng L, Hofr C, Emeson RB, Allain FH
(2010) Cell 143: 225-37
MeSH Terms: Adenosine Deaminase, Amino Acid Sequence, Animals, Cell Line, Humans, Mice, Models, Molecular, Molecular Sequence Data, Mutation, Nuclear Magnetic Resonance, Biomolecular, RNA Precursors, RNA, Double-Stranded, RNA-Binding Proteins, Rats, Receptors, AMPA, Sequence Alignment
Show Abstract · Added May 28, 2014
Sequence-dependent recognition of dsDNA-binding proteins is well understood, yet sequence-specific recognition of dsRNA by proteins remains largely unknown, despite their importance in RNA maturation pathways. Adenosine deaminases that act on RNA (ADARs) recode genomic information by the site-selective deamination of adenosine. Here, we report the solution structure of the ADAR2 double-stranded RNA-binding motifs (dsRBMs) bound to a stem-loop pre-mRNA encoding the R/G editing site of GluR-2. The structure provides a molecular basis for how dsRBMs recognize the shape, and also more surprisingly, the sequence of the dsRNA. The unexpected direct readout of the RNA primary sequence by dsRBMs is achieved via the minor groove of the dsRNA and this recognition is critical for both editing and binding affinity at the R/G site of GluR-2. More generally, our findings suggest a solution to the sequence-specific paradox faced by many dsRBM-containing proteins that are involved in post-transcriptional regulation of gene expression.
Copyright © 2010 Elsevier Inc. All rights reserved.
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16 MeSH Terms
ADAR1 and ADAR2 expression and editing activity during forebrain development.
Jacobs MM, Fogg RL, Emeson RB, Stanwood GD
(2009) Dev Neurosci 31: 223-37
MeSH Terms: Adenosine Deaminase, Animals, Embryo, Mammalian, Fluorescent Antibody Technique, Immunohistochemistry, Male, Mice, Neurogenesis, Prosencephalon, RNA Editing, RNA, Messenger, RNA-Binding Proteins, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added July 12, 2010
The conversion of adenosine to inosine within RNA transcripts is regulated by a family of double-stranded RNA-specific adenosine deaminases referred to as adenosine deaminases that act on RNA (ADARs). Little is known regarding the developmental expression of ADAR family members or the mechanisms responsible for the specific patterns of editing observed for ADAR substrates. We have examined the spatiotemporal expression patterns for ADAR1 and ADAR2 in mouse forebrain. ADAR1 and ADAR2 are broadly distributed in most regions of the mouse forebrain by P0, including the cerebral cortex, hippocampus, and diencephalon. High expression levels were maintained into adulthood. Colocalization studies demonstrated ADAR1 and ADAR2 expression in neurons but not astrocytes. Editing for specific ADAR mRNA targets precedes high expression of ADAR proteins, suggesting that region-specific differences in editing patterns may not be mediated solely by ADAR expression levels.
2009 S. Karger AG, Basel.
1 Communities
2 Members
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13 MeSH Terms
RNA editing as a therapeutic target for CNS disorders.
Morabito MV, Emeson RB
(2009) Neuropsychopharmacology 34: 246
MeSH Terms: Adenosine Deaminase, Animals, Central Nervous System Diseases, Humans, RNA Editing
Added July 12, 2010
1 Communities
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5 MeSH Terms
Adenosine receptors in regulation of dendritic cell differentiation and function.
Novitskiy SV, Ryzhov S, Zaynagetdinov R, Goldstein AE, Huang Y, Tikhomirov OY, Blackburn MR, Biaggioni I, Carbone DP, Feoktistov I, Dikov MM
(2008) Blood 112: 1822-31
MeSH Terms: Adenosine, Adenosine A2 Receptor Antagonists, Adenosine Deaminase, Animals, Base Sequence, Cell Differentiation, DNA Primers, Dendritic Cells, Humans, Immune Tolerance, Inflammation Mediators, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasms, Experimental, Neovascularization, Pathologic, Purinergic P1 Receptor Antagonists, Receptor, Adenosine A2B, Receptors, Purinergic P1, Signal Transduction
Show Abstract · Added December 10, 2013
Differentiation of functional dendritic cells (DCs) critically depends on the microenvironment. DCs differentiate in hypoxic tumor sites and inflamed or damaged tissue. Because local concentrations of adenosine reach high physiologically relevant levels in these conditions, we assessed the expression of adenosine receptors and the effect of their activation on differentiation of human monocytes and mouse peritoneal macrophages and hematopoietic progenitor cells (HPCs) into myeloid DCs. Stimulation of adenosine receptors skews DC differentiation toward a distinct cell population characterized by expression of both DC and monocyte/macrophage cell surface markers. Pharmacologic analysis and experiments with cells from A(2B) adenosine receptor knockout mice identified A(2B) receptor as the mediator of adenosine effects on DCs. Unlike normal myeloid DCs, adenosine-differentiated DCs have impaired allostimulatory activity and express high levels of angiogenic, pro-inflammatory, immune suppressor, and tolerogenic factors, including VEGF, IL-8, IL-6, IL-10, COX-2, TGF-beta, and IDO. They promoted tumor growth if injected into tumors implanted in mice. Using adenosine desaminase knockout animals, we showed that DCs with proangiogenic phenotype are highly abundant under conditions associated with elevated levels of extracellular adenosine in vivo. Adenosine signaling through A(2B) receptor is an important factor of aberrant DC differentiation and generation of tolerogenic, angiogenic, and proinflammatory cells.
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21 MeSH Terms