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Phenotypic defects at 24 hpf caused by adar knockdown and overexpression a Wild-type (b, c) Adar MO-injected embryos develop abnormal phenotype in the posterior part with disturbed body axis, shortened tail and crooked, disorganized notochord. d MO phenotype can be fully rescued with wild-type mRNA injection. e Mutant adar mRNA E1030A with inactivated editing domain could not rescue the malformed phenotype. f, g Phenotype defects caused by adar mRNA overexpression. The anterior defects, including cyclopia and head malformations are mRNA dose dependent. Inset marked by red boxes denotes overlaid identical image taken at different focal plane. Observation was performed on embryos from four independent adult pairs with similar results. h, i Injection statistics of Adar MO, rescue, and mRNA overexpression. Source data are provided in the Source data file.
Source publication
Adenosine deaminases (ADARs) catalyze the deamination of adenosine to inosine, also known as A-to-I editing, in RNA. Although A-to-I editing occurs widely across animals and is well studied, new biological roles are still being discovered. Here, we study the role of A-to-I editing in early zebrafish development. We demonstrate that Adar, the zebraf...
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Background
Adenosine deaminase (ADA) via two isoenzymes, ADA1 and ADA2, regulates intra- and extracellular adenosine concentrations by converting it to inosine. In the central nervous system (CNS), adenosine modulates the processes of neuroinflammation and demyelination that together play a critical role in the pathophysiology of multiple sclerosis...
Citations
... Our subsequent filtering steps, illustrated in Fig. 1A and Additional file 2: Fig. S1, resulted in a set of 17,874 high-confidence RNA editing sites, of which 15,109 were A-to-I editing sites, making up 84.53% of the entire set (Fig. 1B; Additional file 1: Supplementary Tables 2 and 3). This proportion is in line with prior research findings [25,26]. Among these A-to-I editing sites, 8104 were previously reported by REDIportal, while the remaining 7005 were newly discovered, and both exhibited a similar motif pattern (Additional file 2: Fig. S2 and Fig. S3). ...
... Yang et al. BMC Biology (2024) 22:106 Discussion ADAR-mediated A-to-I editing has been established as crucial for the normal development of organisms [26,35,36]. Disruptions to ADAR can lead to serious consequences such as locomotion and neuron defects seen in flies with mutant ADAR [37,38]. ...
Background
The significance of A-to-I RNA editing in nervous system development is widely recognized; however, its influence on retina development remains to be thoroughly understood.
Results
In this study, we performed RNA sequencing and ribosome profiling experiments on developing mouse retinas to characterize the temporal landscape of A-to-I editing. Our findings revealed temporal changes in A-to-I editing, with distinct editing patterns observed across different developmental stages. Further analysis showed the interplay between A-to-I editing and alternative splicing, with A-to-I editing influencing splicing efficiency and the quantity of splicing events. A-to-I editing held the potential to enhance translation diversity, but this came at the expense of reduced translational efficiency. When coupled with splicing, it could produce a coordinated effect on gene translation.
Conclusions
Overall, this study presents a temporally resolved atlas of A-to-I editing, connecting its changes with the impact on alternative splicing and gene translation in retina development.
... This later function was uncovered after ADAR mutations were identified in patients suffering from autoimmune disorders [11], and additional studies demonstrated that loss of dsRNA sensors rescues lethality of ADAR mutations in mice [12][13][14]. Furthermore, as ADARs are conserved in metazoans, studies from several model organisms have explored these relationships and provide data that link ADAR loss with changes in immune gene expression [15][16][17]. However, studies on the susceptibility of ADAR mutant animals to infection are largely lacking. ...
Background
In all organisms, the innate immune system defends against pathogens through basal expression of molecules that provide critical barriers to invasion and inducible expression of effectors that combat infection. The adenosine deaminase that act on RNA (ADAR) family of RNA-binding proteins has been reported to influence innate immunity in metazoans. However, studies on the susceptibility of ADAR mutant animals to infection are largely lacking.
Results
Here, by analyzing adr-1 and adr-2 null mutants in well-established slow-killing assays, we find that both Caenorhabditis elegans ADARs are important for organismal survival to gram-negative and gram-positive bacteria, all of which are pathogenic to humans. Furthermore, our high-throughput sequencing and genetic analysis reveal that ADR-1 and ADR-2 function in the same pathway to regulate collagen expression. Consistent with this finding, our scanning electron microscopy studies indicate adr-1;adr-2 mutant animals also have altered cuticle morphology prior to pathogen exposure.
Conclusions
Our data uncover a critical role of the C. elegans ADAR family of RNA-binding proteins in promoting cuticular collagen expression, which represents a new post-transcriptional regulatory node that influences the extracellular matrix. In addition, we provide the first evidence that ADAR mutant animals have altered susceptibility to infection with several opportunistic human pathogens, suggesting a broader role of ADARs in altering physical barriers to infection to influence innate immunity.
... Table 1). This is in line with previous research findings 32,33 . Given that A-to-I editing is the most prevalent type of editing and has significant impacts on development 34-36 , we chose to focus our subsequent analysis solely on this type of editing. ...
... Adar-mediated A-to-I editing has been established as crucial for normal development of organisms 33,43,44 . Disruptions to Adar can lead to serious consequences such as locomotion and neuron defects seen in flies with mutant Adar 45 . ...
The significance of A-to-I RNA editing in neurological development is widely recognized, however, its influence on retina development remains to be thoroughly understood. In this study, we aimed to characterize the temporal landscape of A-to-I editing in mouse retina development using total RNA-seq and Ribosome profiling, with a specific emphasis on its effect on gene translation. Our findings revealed that the editing underwent plastic changes and distinct editing contents facilitated stage-specific functions. Further analysis showed a dynamic interplay between A-to-I editing and alternative splicing, with A-to-I editing having a significant impact on splicing efficiency and increasing the quantity of splicing events. A-to-I editing held the potential of enhancing the translatome's diversity, but this came at the expense of reduced translational efficiency. When coupled with splicing, it could produce a coordinated regulatory effect on translatome dynamics. Overall, our study presents a temporally resolved atlas of A-to-I editing, connecting its dynamic changes with the regulatory impact on splicing and translation.
Cardiovascular diseases (CVDs) are the leading cause of mortality and disability worldwide. Numerous studies have demonstrated that non-coding RNAs (ncRNAs) play a primary role in CVD development. Therefore, studies on the mechanisms of ncRNAs are essential for further efforts to prevent and treat CVDs. Small nucleolar RNAs (snoRNAs) are a novel species of non-conventional ncRNAs that guide post-transcriptional modifications and the subsequent maturation of small nuclear RNA and ribosomal RNA. Evidently, snoRNAs are extensively expressed in human tissues and may regulate different illnesses. Particularly, as the next-generation sequencing techniques have progressed, snoRNAs have been shown to be differentially expressed in CVDs, suggesting that they may play a role in the occurrence and progression of cardiac illnesses. However, the molecular processes and signaling pathways underlying the function of snoRNAs remain unidentified. Therefore, it is of great value to comprehensively investigate the association between snoRNAs and CVDs. The aim of this review was to collate existing literature on the biogenesis, characteristics, and potential regulatory mechanisms of snoRNAs. In particular, we present a scientific update on these snoRNAs and their relevance to CVDs in an effort to cast new light on the functions of snoRNAs in the clinical diagnosis of CVDs.
Background
Xenopus has served as a valuable model system for biomedical research over the past decades. Notably, ADAR was first detected in frog oocytes and embryos as an activity that unwinds RNA duplexes. However, the scope of A-to-I RNA editing by the ADAR enzymes in Xenopus remains underexplored.
Results
Here, we identify millions of editing events in Xenopus with high accuracy and systematically map the editome across developmental stages, adult organs, and species. We report diverse spatiotemporal patterns of editing with deamination activity highest in early embryogenesis before zygotic genome activation and in the ovary. Strikingly, editing events are poorly conserved across different Xenopus species. Even sites that are detected in both X. laevis and X. tropicalis show largely divergent editing levels or developmental profiles. In protein-coding regions, only a small subset of sites that are found mostly in the brain are well conserved between frogs and mammals.
Conclusions
Collectively, our work provides fresh insights into ADAR activity in vertebrates and suggest that species-specific editing may play a role in each animal’s unique physiology or environmental adaptation.
Cardiovascular diseases (CVDs) are a group of diseases that have a major impact on global health and are the leading cause of death. A large number of chemical base modifications in ribonucleic acid (RNA) are associated with cardiovascular diseases. A variety of ribonucleic acid modifications exist in cells, among which adenosine deaminase-dependent modification is one of the most common ribonucleic acid modifications. Adenosine deaminase acting on ribonucleic acid 1 (Adenosine deaminase acting on RNA 1) is a widely expressed double-stranded ribonucleic acid adenosine deaminase that forms inosine (A-to-I) by catalyzing the deamination of adenosine at specific sites of the target ribonucleic acid. In this review, we provide a comprehensive overview of the structure of Adenosine deaminase acting on RNA 1 and summarize the regulatory mechanisms of ADAR1-mediated ribonucleic acid editing in cardiovascular diseases, indicating Adenosine deaminase acting on RNA 1 as a promising therapeutic target in cardiovascular diseases.
Background
In all organisms, the innate immune system defends against pathogens through basal expression of molecules that provide critical barriers to invasion and inducible expression of effectors that combat infection. The adenosine deaminase that act on RNA (ADAR) family of RNA binding proteins has been reported to influence innate immunity in metazoans. However, studies on the susceptibility of ADAR mutant animals to infection are largely lacking.
Results
Here, by analyzing adr-1 and adr-2 null mutants in well-established slow-killing assays, we find that both Caenorhabditis elegans ADARs are important for organismal survival to gram-negative and gram-positive bacteria, all of which are pathogenic to humans. Furthermore, our high-throughput sequencing and genetic analysis reveal that ADR-1 and ADR-2 function in the same pathway to regulate collagen expression. Consistent with this finding, our scanning electron microscopy studies indicate adr-1 ; adr-2 mutant animals also have altered cuticle morphology prior to pathogen exposure.
Conclusions
Our data uncover a critical role of the C. elegans ADAR family of RNA binding proteins in promoting cuticular collagen expression, which represents a new post-transcriptional regulatory node that influences the extracellular matrix. In addition, we provide the first evidence that ADAR mutant animals have altered susceptibility to infection with several opportunistic human pathogens, suggesting a broader role of ADARs in altering physical barriers to infection to influence innate immunity.
Background
The effects of polystyrene nanoplastic (PS-NP) on the human body is a matter of global concern, as they are mainly absorbed through the food chain after release into the water ecosystem. In this study, mucin (Mu) was extracted from Aurelia aurita and its effect to reduce the toxicity of PS-NP present in water was verified. However, the effect of Mu on genotoxicity was not verified.Objective
Zebrafish embryos were exposed to PS-NP, Mu, and Mu + PS-NP to verify their effects on genotoxicity. Based on the subsequent phenotypic anomalies in the juvenile fish, mRNA sequencing (mRNA-seq) was employed to determine the changes in the levels of gene transcription induced by PS-NP.ResultsCompared with the control group, the experimental group exposed to Mu or PS-NP + Mu showed no specific variations in phenotypic anomalies. In contrast, the experimental group exposed to PS-NP alone showed effects, such as pericardial edema, yolk-sac edema, thicker yolk, tail deformity, and spinal curvature. Analyses of differentially expressed genes (DEGs) indicated that changes in gene expression occurred in 340, 16, and 17 genes in the PS-NP, Mu, and PS-NP + Mu groups, respectively.Conclusion
Our results showed that PS-NP induced changes in mRNA expression and had toxic effects that caused phenotypic anomalies in the zebrafish embryos. However, further studies are necessary to investigate the effects of different types of plastic and properties on genotoxicity and phenotypic anomalies in aquatic organisms. A trend of reduction was found in genotoxicity and phenotypic anomalies when the embryos were exposed to PS-NP together with Mu, suggesting that Mu extracted from Aurelia aurita could reduce the genotoxicity of PS-NP.
