Consistent levels of A-to-I RNA editing across individuals in coding sequences and non-conserved Alu repeats

Greenberger, Shoshana; Levanon, Erez Y.; Paz-Yaacov, Nurit; Barzilai, Aviv; Safran, Michal; Osenberg, Sivan; Amariglio, Ninette; Rechavi, Gideon; Eisenberg, Eli

doi:10.1186/1471-2164-11-608

Cited by 34 publications

(26 citation statements)

References 41 publications

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“…As reflected by low variability in our data, we observed highly consistent levels of editing at all iGluR sites across individuals, which is in line with the results of recent studies that assessed editing in different molecules. 31,32 These results confirm that, as was reported for other targets, RNA editing of iGluRs is a tightly regulated process, emphasizing the importance of this posttranscriptional modification for the functionality of the glutamatergic system in the brain. 32 However, we did not detect any diagnosis-or suicide-specific alterations.…”

Section: Discussionsupporting

confidence: 76%

Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

Lyddon

Navarrett²,

Dracheva³

2012

jpn

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IntroductionGlutamate is the main neurotransmitter responsible for excitatory neurotransmission throughout the brain. Glutamate serves as a ligand for G-protein coupled metabotropic and ionotropic (iGluRs) receptors. The latter consists of N-methyl-D-aspartate, α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate (KA) subtypes. Glutamate dysfunction has been linked to numerous diseases, including schizophrenia, bipolar disorder and major depressive disorder. 1-6The AMPA and KA receptors are ligand-gated nonselective cation channels that mediate fast excitatory neurotransmission. Each receptor is a tetramer composed of a combination of subunits encoded by separate genes, GluA1-4 for AMPA, and GluK1-3 and KA1-2 for KA receptors. Individual subunit transcripts undergo posttranscriptional modifications that substantially alter the structure and function of the resulting receptors. Alternative splicing of GluA1-4 generates 2 different variants of each subunit (flip or flop), forming AMPA receptors with distinct kinetic properties. [7][8][9] In addition, AMPA and KA receptor transcripts can be modified by RNA editing. 10The most frequent RNA editing process in eukaryotes involves conversion of adenosine to inosine catalyzed by the adenosine deaminases acting on RNA (ADAR) enzymes.11 As inosine is interpreted as a guanosine during splicing and translation, the editing event can result in recoding. A total of Background: Dysfunction of glutamate neurotransmission has been implicated in the pathology of schizophrenia and bipolar disorder, and one mechanism by which glutamate signalling can be altered is through RNA editing of ionotropic glutamate receptors (iGluRs). The objectives of the present study were to evaluate the editing status of iGluRs in the human prefrontal cortex, determine whether iGluR editing is associated with psychiatric disease or suicide and evaluate a potential association between editing and alternative splicing in the α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) iGluR subunits' pre-mRNA. Methods: We studied specimens derived from patients with antemortem diagnoses of bipolar disorder (n = 31) or schizophrenia (n = 34) who died by suicide or other causes, and from psychiatrically healthy controls (n = 34) who died from causes other than suicide. The RNA editing at all 8 editing sites within AMPA (GluA2-4 subunits) and kainate (GluK1-2 subunits) iGluRs was analyzed using a novel real-time quantitative polymerase chain reaction assay. Results: No differences in editing were detected among schizophrenia, bipolar or control groups or between suicide completers and patients who died from causes other than suicide. The editing efficiency was significantly higher in the flop than in the flip splicoforms of GluA3-4 AMPA subunits (all p < 0.001). Limitations: The study is limited by the near absence of specimens from medicationnaive psychiatric patients and considerable variation in medication regimens among individuals, both of which introduce considerable uncertainty into the ana...

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Section: Discussionsupporting

confidence: 76%

Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

Lyddon

Navarrett²,

Dracheva³

2012

jpn

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“…Previous studies in humans have shown only limited effects of genetic variation on RNA editing. In one study, six A-to-I editing sites were found to be edited consistently across 32 individuals (Greenberger et al 2010). Another study found evidence of genetic variation for two (of 7389) A-to-I editing sites (Daneck et al 2012).…”

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confidence: 99%

Genetic Architectures of Quantitative Variation in RNA Editing Pathways

Gatti

Srivastava

et al. 2015

Genetics

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RNA editing refers to post-transcriptional processes that alter the base sequence of RNA. Recently, hundreds of new RNA editing targets have been reported. However, the mechanisms that determine the specificity and degree of editing are not well understood. We examined quantitative variation of site-specific editing in a genetically diverse multiparent population, Diversity Outbred mice, and mapped polymorphic loci that alter editing ratios globally for C-to-U editing and at specific sites for A-to-I editing. An allelic series in the C-to-U editing enzyme Apobec1 influences the editing efficiency of Apob and 58 additional C-to-U editing targets. We identified 49 A-to-I editing sites with polymorphisms in the edited transcript that alter editing efficiency. In contrast to the shared genetic control of C-to-U editing, most of the variable A-to-I editing sites were determined by local nucleotide polymorphisms in proximity to the editing site in the RNA secondary structure. Our results indicate that RNA editing is a quantitative trait subject to genetic variation and that evolutionary constraints have given rise to distinct genetic architectures in the two canonical types of RNA editing.KEYWORDS genetics; RNA editing; Diversity Outbred; Apobec1; secondary structure; Multiparent Advanced Generation Inter-Cross (MAGIC); multiparental populations; MPP R NA EDITING in mammals occurs through deamination of adenosine, which is converted to inosine (A-to-I editing), or deamination of cytosine, which is converted to uracil (C-to-U editing) (Davidson and Shelness 2000;Bass 2002). Other types of editing have been reported, but these findings remain controversial (Bass et al. 2012;Gu et al. 2012). The two canonical editing types, A-to-I and C-to-U editing, are mediated by distinct pathways. A-to-I editing is catalyzed on double-stranded (ds) RNA by proteins in the adenosine deaminase, RNA-specific (ADAR) family (ADAR1 and ADAR2) and is most common in neuronal tissues. However, the Adar gene family is ubiquitously expressed, and editing has been reported in many other tissues (Gu et al. 2012).Homozygous deletion of Adar genes is embryonic lethal in mice, and defects in A-to-I editing have been associated with neurodegenerative disorders and cancers (Gurevich et al. 2002;Paz et al. 2007). The C-to-U editing pathway is catalyzed by apolipoprotein B messenger RNA (mRNA) editing enzyme catalytic polypeptide 1 (Apobec1), which is expressed primarily in small intestine and liver, where it targets the transcript of apolipoprotein B (Apob), converting a CAA (glutamine) codon within the coding sequence to a stop codon (UAA). This editing event results in two APOB protein isoforms, APOB48 from the edited transcript and APOB100 from the unedited transcript. Editing of Apob is evolutionarily conserved and occurs in mice, humans, and other mammals. The edited isoform APOB48 functions in the synthesis, assembly, and secretion of chylomicrons in the small intestine; the unedited isoform APOB100 is expressed in the liver and gives ris...

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“…For example, editing of specific adenosines within Alu repeats located in long double-stranded regions of human mRNAs occurs to a similar extent among different human individuals. 30 In addition, despite the presence of 2 homologous editing enzymes in mammals, certain adenosines in repetitive elements are specifically edited by only one of the ADAR enzymes. 31 Furthermore, editing site selection within noncoding regions appears to be regulated.…”

Section: Introductionmentioning

confidence: 99%

Noncoding regions ofC. elegansmRNA undergo selective adenosine to inosine deamination and contain a small number of editing sites per transcript

et al. 2015

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ADARs (Adenosine deaminases that act on RNA) "edit" RNA by converting adenosines to inosines within doublestranded regions. The primary targets of ADARs are long duplexes present within noncoding regions of mRNAs, such as introns and 3 0 untranslated regions (UTRs). Because adenosine and inosine have different base-pairing properties, editing within these regions can alter splicing and recognition by small RNAs. However, despite numerous studies identifying multiple editing sites in these genomic regions, little is known about the extent to which editing sites cooccur on individual transcripts or the functional output of these combinatorial editing events. To begin to address these questions, we performed an ultra-deep sequencing analysis of 4 Caenorhabditis elegans 3 0 UTRs that are known ADAR targets. Synchronous editing events were determined for the long duplexes in vivo. Furthermore, the validity of each editing event was confirmed by sequencing the same regions of mRNA from worms that lack A-to-I editing. This analysis identified a large number of editing sites that can occur within each 3 0 UTR, but interestingly, each individual transcript contained only a small fraction of these A-to-I editing events. In addition, editing patterns were not random, indicating that an editing event can affect the efficiency of editing at subsequent adenosines. Furthermore, we identified specific sites that can be both positively and negatively correlated with additional sites leading to mutually exclusive editing patterns. These results suggest that editing in noncoding regions is selective and hyper-editing of cellular RNAs is rare.

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Consistent levels of A-to-I RNA editing across individuals in coding sequences and non-conserved Alu repeats

Cited by 34 publications

References 41 publications

Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

Genetic Architectures of Quantitative Variation in RNA Editing Pathways

Noncoding regions ofC. elegansmRNA undergo selective adenosine to inosine deamination and contain a small number of editing sites per transcript

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