Canonical A-to-I and C-to-U RNA Editing Is Enriched at 3′UTRs and microRNA Target Sites in Multiple Mouse Tissues

Gu, Tongjun; Buaas, F. William; Simons, Allen K.; Ackert‐Bicknell, Cheryl; Braun, Robert E.; Hibbs, Matthew A.

doi:10.1371/journal.pone.0033720

Cited by 77 publications

(77 citation statements)

References 28 publications

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“…In addition, most of the A-to-G RNA variants observed in the single cells occurred in the intronic regions and UTRs (Fig. 3C), in agreement with previous A-to-G RNA editing studies (24,26,27).…”

Section: Rna Variation Is Similar In Drug-tolerant Cells and Other Casupporting

confidence: 92%

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing

Lee

López-Díaz

Khan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

168

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The acute cellular response to stress generates a subpopulation of reversibly stress-tolerant cells under conditions that are lethal to the majority of the population. Stress tolerance is attributed to heterogeneity of gene expression within the population to ensure survival of a minority. We performed whole transcriptome sequencing analyses of metastatic human breast cancer cells subjected to the chemotherapeutic agent paclitaxel at the single-cell and population levels. Here we show that specific transcriptional programs are enacted within untreated, stressed, and drugtolerant cell groups while generating high heterogeneity between single cells within and between groups. We further demonstrate that drug-tolerant cells contain specific RNA variants residing in genes involved in microtubule organization and stabilization, as well as cell adhesion and cell surface signaling. In addition, the gene expression profile of drug-tolerant cells is similar to that of untreated cells within a few doublings. Thus, single-cell analyses reveal the dynamics of the stress response in terms of cell-specific RNA variants driving heterogeneity, the survival of a minority population through generation of specific RNA variants, and the efficient reconversion of stress-tolerant cells back to normalcy.

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Section: Rna Variation Is Similar In Drug-tolerant Cells and Other Casupporting

confidence: 92%

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing

Lee

López-Díaz

Khan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

168

150

View full text Add to dashboard Cite

show abstract

“…Until now, only a few recoding RNA editing events (e.g., Q/R site editing in the glutamate receptor) have been verified. The editing events within 3 0 UTRs can affect transcript stability via affecting microRNA targeting or the nuclear retention of transcripts (26)(27)(28)(29). However, the editing targets within coding region will cause amino acid change and affect protein function rather than protein level, suggesting that the recoding editing events are of high potentials to play a role in tumorigenesis by either inactivating a tumor suppressor or activating genes that promote tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Adenosine-to-Inosine RNA Editing Mediated by ADARs in Esophageal Squamous Cell Carcinoma

et al. 2014

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Esophageal squamous cell carcinoma (ESCC), the major histologic form of esophageal cancer, is a heterogeneous tumor displaying a complex variety of genetic and epigenetic changes. Aberrant RNA editing of adenosine-to-inosine (A-to-I), as it is catalyzed by adenosine deaminases acting on RNA (ADAR), represents a common posttranscriptional modification in certain human diseases. In this study, we investigated the status and role of ADARs and altered A-to-I RNA editing in ESCC tumorigenesis. Among the three ADAR enzymes expressed in human cells, only ADAR1 was overexpressed in primary ESCC tumors. ADAR1 overexpression was due to gene amplification. Patients with ESCC with tumoral overexpression of ADAR1 displayed a poor prognosis. In vitro and in vivo functional assays established that ADAR1 functions as an oncogene during ESCC progression. Differential expression of ADAR1 resulted in altered gene-specific editing activities, as reflected by hyperediting of FLNB and AZIN1 messages in primary ESCC. Notably, the edited form of AZIN1 conferred a gain-of-function phenotype associated with aggressive tumor behavior. Our findings reveal that altered gene-specific A-to-I editing events mediated by ADAR1 drive the development of ESCC, with potential implications in diagnosis, prognosis, and treatment of this disease. Cancer Res; 74(3); 840-51. Ó2013 AACR.

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“…Next-generation sequencing and bioinformatic technologies have recently been used to identify millions of RNA editing events at the genome scale in humans Ramaswami et al 2012Ramaswami et al , 2013Bazak et al 2014), mice (Danecek et al 2012;Gu et al 2012), and fruit flies (Graveley et al 2011). However, the RNA editome in C. elegans remains largely unknown.…”

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confidence: 99%

Profiling the RNA editomes of wild-type C. elegans and ADAR mutants

et al. 2014

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RNA editing increases transcriptome diversity through post-transcriptional modifications of RNA. Adenosine deaminases that act on RNA (ADARs) catalyze the adenosine-to-inosine (A-to-I) conversion, the most common type of RNA editing in higher eukaryotes. Caenorhabditis elegans has two ADARs, ADR-1 and ADR-2, but their functions remain unclear. Here, we profiled the RNA editomes of C. elegans at different developmental stages of wild-type and ADAR mutants. We developed a new computational pipeline with a ''bisulfite-seq-mapping-like'' step and achieved a threefold increase in identification sensitivity. A total of 99.5% of the 47,660 A-to-I editing sites were found in clusters. Of the 3080 editing clusters, 65.7% overlapped with DNA transposons in noncoding regions and 73.7% could form hairpin structures. The numbers of editing sites and clusters were highest at the L1 and embryonic stages. The editing frequency of a cluster positively correlated with the number of editing sites within it. Intriguingly, for 80% of the clusters with 10 or more editing sites, almost all expressed transcripts were edited. Deletion of adr-1 reduced the editing frequency but not the number of editing clusters, whereas deletion of adr-2 nearly abolished RNA editing, indicating a modulating role of ADR-1 and an essential role of ADR-2 in A-to-I editing. Quantitative proteomics analysis showed that adr-2 mutant worms altered the abundance of proteins involved in aging and lifespan regulation. Consistent with this finding, we observed that worms lacking RNA editing were short-lived. Taken together, our results reveal a sophisticated landscape of RNA editing and distinct modes of action of different ADARs.

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Canonical A-to-I and C-to-U RNA Editing Is Enriched at 3′UTRs and microRNA Target Sites in Multiple Mouse Tissues

Cited by 77 publications

References 28 publications

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing

Adenosine-to-Inosine RNA Editing Mediated by ADARs in Esophageal Squamous Cell Carcinoma

Profiling the RNA editomes of wild-type C. elegans and ADAR mutants

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