Then, it was found that mRNA transcripts appeared to be shorter than their corresponding genes. In fact, the protein coding information in genes is interrupted by non-coding sequences called introns, which results in "split genes.
The process of RNA splicing involves removing non-coding regions, introns, and splicing together adjacent coding regions, exons. Funded by The Josiah Macy, Jr. All rights reserved. USA 92 , — Matthews, M. Nature Struct.
Katrekar, D. Nature Methods 16 , — Abudayyeh, O. Science , — Download references. Article 10 NOV Technology Feature 09 NOV Article 03 NOV Technology Feature 01 NOV Francis Crick Institute. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Advanced search. Skip to main content Thank you for visiting nature. You have full access to this article via your institution. Download PDF. A role for RNA A foundational tenet in molecular genetics — its central dogma — was that cellular machinery faithfully transcribes genetic information from a double-stranded DNA template into a single-stranded RNA messenger, which is then translated into a protein.
References 1. PubMed Article Google Scholar 2. PubMed Article Google Scholar 3. PubMed Article Google Scholar 4. PubMed Article Google Scholar 5. PubMed Article Google Scholar 6.
Figure 5. The color of the first arrow in each pathway indicates the mechanism refer to Figure 1 by which ADAR1 regulates its direct targets, depicted in pink shapes. Additional activators of specific pathway steps are depicted in red rounded rectangles. ADAR1's role to attenuate an aberrant innate immune response has been well established 93 , Independent of its involvement in the regulation of the immune system, ADAR1 also plays critical roles regulating the development and homeostasis of multiple organs, including the spleen, small intestine, and kidney These observations suggest that ADAR1 could impact metabolic functions in a systematic manner affecting multiple organs, possibly through its RNA-editing capability.
The links between circadian rhythms, sleep, and metabolism have been strengthened in recent years and presented as viable targets of therapeutic intervention for metabolic diseases 98 , A recent study, using Drosophila melanogaster as the model, demonstrated that deficiencies in ADAR1 results in synaptic dysfunction in glutamatergic neurons and sustained release of neurotransmitter to promote sleep It underlines the variety of mechanisms ADAR1 could exploit to control an individual's susceptibility to metabolic disorders.
Despite this hint, a decade would pass before ADAR2 was directly connected to the metabolic functions of the pancreas Figure 6. Activated ADAR2 in turn promotes the secretion of insulin from the pancreas by influencing the expression of key factors involved in exocytosis Figure 6. CVD, cardiovascular disease. Certain metabolic diseases, such as diabetes or obesity, can manifest in the condition of hyperuricemia abnormally high uric acid level.
Interestingly, increased levels of uric acid were detected in the cortex of ADAR2-knockout mice Hyperuricemia mediated by the loss of ADAR2 in the cortex correlates with the induction of phosphoribosyl pyrophosphate synthetase 1 PRPS1 , an essential enzyme involved in the synthesis of uric acid.
Due to ADAR2's role in facilitating insulin secretion upon nutrient stimulation and reducing uric acid levels, one would assume that ADAR2 might be an active gate-keeper to prevent metabolic diseases. ADAR2-transgenic mice, however, develop hyperglycemia and severe obesity ADAR2-induced obesity in transgenic mice is the result of altered behavior patterns presented in the form of addictive overeating hyperphagia , In another study, transgenic mice solely expressing the fully-edited isoform of 5-HT 2c R developed phenotypic characteristics of Prader-Willi syndrome PWS , including hyperphagia PWS is a genetic imprinting disorder that manifests in hyperphagia, early-onset obesity and diabetes.
ADAR2 contributes to circadian clock maintenance through a couple mechanisms. ADAR2-knockout mice display disrupted rhythms of fatty acid metabolism and gain excessive weight with a high-fat diet, highlighting the significance of ADAR2 at the intersection between circadian rhythm and metabolic regulation. Other than its preferred presence in the brain and inability to catalyze RNA editing on any proven target, little is known about ADAR3's functional connections to human diseases, including metabolic disorders.
The aforementioned study in glioblastoma suggests a similar role for ADAR3 in metabolic diseases, as an inhibitor of RNA editing mediated by other active editases Despite the lack of mechanistic data, the large amount of genetic information available from the general population has shed some light on potential connections between ADAR3 and metabolism.
Moreover, this association was later linked to a variety of metabolic parameters, including abdominal circumference, body mass index and serum triglyceride level While the correlation between ADAR3 and aging was preliminarily demonstrated in mutant strains of Caenorhabditis elegans , more sophisticated models are needed to establish ADAR3's functional role in aging and metabolic regulation Unedited and edited apoB encodes for a full-length form apoB and a truncated form apoB48, respectively.
ApoB is synthesized in the liver and is a part of the assembly of low density lipoprotein LDL and very low density lipoprotein VLDL , while apoB48 is mostly produced in the intestine and is required for chylomicron formation and fat absorption Figure 7.
The color of the first arrow in each pathway indicates the mechanism refer to Figure 1 by which APOBEC1 regulates its direct targets, depicted in pink shapes. Gray arrows point to ApoB-associated secondary functions. A transgenic rabbit model with reduced expression of APOBEC1 presented a lean phenotype compared to wild type when challenged with a high-fat diet In an apoE-deficient mouse model, apoB48 promotes higher levels of cholesterol accumulation and atherosclerotic lesion formation.
This phenotype is the manifestation of apoB48 being cleared exclusively through apoE, while apoB can be cleared through the LDL receptor alone , On the other hand, links between apoB and obesity and diabetes have also been established.
In rodent models fed high-fat diets, accumulation of apoB in the liver induces endoplasmic reticulum ER stress and insulin resistance , This phenotype is caused by JNK-mediated phosphorylation of insulin receptor substrate IRS-1 , a connection known to link ER stress, obesity and diabetes Numerous examples mentioned in this review fit this description providing multiple intervention points, including modulation of the levels and activity of editases, as well as correction of the edited target s.
There are, however, plenty of ambiguities in the world of RNA editing. In the context of A-to-I editing, many disease-relevant editing targets lack clear identification of the responsible editase s.
In cases where involvement of editases were confirmed, the relationships among editases could be complicated. The functional difference between the two ADAR1 isoforms, p and p, is also an important factor to consider when determining ADAR1's role in human disease. Earlier studies characterized p as constitutively expressed, while p is interferon-inducible and the main isoform responsible for innate immune response modulation and AGS 93 , 95 , , In the context of cancers and metabolic diseases, not all ADAR1-related studies have clearly differentiated the involvement between p and p, creating potential issues to pinpoint the underlying mechanisms.
As our understanding of functional distinctions between p and p improves overtime, there will be a need to revisit their individual roles in different diseases 97 , — Further, albeit indirect, evidence to support these hypotheses is the recent realization that ADARs, well-known for their RNA editing functions, are also capable of performing DNA editing , The effects between RNA and DNA editing can be distinguished through careful planning and execution of sequencing strategies. RNA editing-independent functions of RNA editases play prominent roles in the processes of proliferation, metastasis, and immune evasion during tumorigenesis 49 , — This approach has helped identify these non-catalytic functions beyond the confines of miRNA biogenesis.
However, APOBEC-mediated functions that don't require its deaminase domains have been reported in humans and other species , As more functional studies of RNA editases are reported, clear differentiations between RNA editing-dependent and —independent mechanisms will be necessary to adequately assess their contributions to the development of cancers and metabolic diseases.
RNA-editing events are subjected to highly precise regulatory mechanisms. Mechanisms that regulate general localization and expression of RNA editases have been well-studied 9 , Functional regulation of RNA editing in the context of cancer and metabolic disease, however, remains a gap in our knowledge. Depending on the tissue of origin and disease stage, different cancers have been associated with overall induction or reduction of RNA-editing levels 12 , 13 , Even in diseases with either a clear overall editing profile hyper- vs.
Moreover, alterations of a single editase do not always yield the same result, as demonstrated by the aforementioned pro- and anti-tumorigenic functions displayed by both ADAR1 and ADAR2 in different cancers.
More dramatic examples can be found in situations where the same editing event leads to completely different functional or phenotypic outcomes. APOBEC1-produced apoB48 and its full-length counterpart apoB contribute to developments of atherosclerosis and obesity to different extents based on the surrounding regulatory environment , Even replicating a complex editing profile on one target, such as editing of 5-HT 2c R, could result in opposite phenotypes obesed vs.
Several regulatory mechanisms of RNA editing have been recently identified. These findings also signaled the importance of the splicing machinery in the regulation of RNA editing The end result is a strong correlation between DHX9 expression and tumorigenesis.
Attempts to identify additional enhancers and inhibitors, both intrinsic and extrinsic, of the RNA editing machinery are ongoing. Aside from ACF and RBM47, the physiological significance of these regulators remains to be confirmed beyond in vitro experiments , Pending validation of the involvement of Apobec1-mediated RNA editing in this model, this result suggests that APOBEC1-mediated impact on tumorigenesis is subjected to complex regulatory mechanisms, possibly involving one or more members of the editosome.
More interestingly, the effect of Apobec1 deficiency on TGCT susceptibility was influenced by the context of germ-lineage maternal vs. It suggests that APOBEC1 regulates heritable epigenetic changes, presumably through RNA-editing, to impact the development of human diseases such as testicular cancer It also demonstrated that regulatory mechanisms of RNA editing could impact human diseases by affecting their response to treatments.
Since RNA editing plays a prominent role in cancer development, tumorigenesis-associated pathways and factors could prove to be important regulators of the machinery. For example, tumor suppressor protein TP53 is involved in nearly all aspects of tumorigenesis, but few connections have been made between TP53 and RNA editing A recent study identified IFI16 interferon gamma inducible protein 16 as a common interacting partner of ADAR1 and p53, strengthening this possibility As our understanding of RNA editing in cancers and metabolic disorders improves, it is likely that many other connections will be discovered between RNA editing and established factors associated with these human diseases.
With greater understanding of the relationship between RNA editing and human disease comes the opportunity for innovative therapeutic approaches. RNA-based therapies, which include targeting both RNA itself and its modifications, are becoming viable options to slow down or even reverse the course of human disease — This warrants further investigation of the mechanisms of RNA-editing and including it as an integral part of RNA-based therapies.
Indeed, not only the overall role of RNA editing is being studied in various diseases, but also creative molecular technologies are being developed to identify and verify specific RNA editing events using cell lines or clinical samples 12 , 17 , A recent study integrated genomic, transcriptomic, and proteomic data to pinpoint RNA editing events that are directly responsible for proteomic diversity leading to disease-relevant alterations in cancer samples In principle, modulating the expression or activity of RNA editases is a reasonable strategy for treating diseases driven by dysregulated RNA editing.
To counteract apoBmediated chylomicron formation and lipid absorption, expression of APOBEC1 was reduced to create transgenic rabbits that are resistant to diet-induced obesity Beyond altering the expression of RNA editases, molecular tools are also being developed to perform selective inhibition of RNA editing. In situations where the RNA editing level is inversely correlated with disease progression, promoting RNA editing could have beneficial effects.
Overexpression of APOBEC1 combined with an endothelial functional modulator, SR-BI scavenger receptor, class B, type I , was tested in a cell culture model to show anti-atherogenic potential by altering lipoprotein composition and increasing nitric oxide levels To augment the effect of RNA editing, artificial and manipulatable tools have been engineered to control the RNA editing machinery. By integrating a light-sensitive protection molecule between the editase and the guide RNA, the target—specific RNA editing machinery can be switched on and off via light Proof-of-principle studies have been conducted to demonstrate the potential to target disease-relevant genes and restore proper protein function through RNA editing , Continuous efforts to increase the efficiency, reduce off-target editing, and promote simultaneous editing of multiple targets, will push these technologies closer to therapeutic application , As intriguing as the idea to reverse disease conditions by modulating RNA editing levels, it is not without potential drawbacks.
Since different human diseases are associated with either elevated or reduced levels of RNA editing, altering it one way or the other poses the risk of undesired consequences. For example, it is theoretically possible to modulate the overall levels of inosine-containing RNA by regulating ribonuclease V , But dysregulation of ribonuclease V has been linked to cancers and psychiatric disorders, indicating the potential hazards , In addition to impacting disease progression, RNA editing could also affect drug response.
These studies highlight potential side-effects of both stand-alone and combinatorial therapies involving modulation of RNA editing. Man-made, RNA-guided, and target-specific RNA editing has the potential to become the next revolution in epi genetic therapy. It offers a unique opportunity to modulate protein functions without altering the sequence and integrity of the genome.
Recent studies pointing out the potentially crippling effects of genome editing, however, should serve as a cautionary tale when considering using RNA editing in a similar fashion — Further studies are needed to ensure the efficacy and safety of this approach before considering clinical applications.
Having mentioned the potential problems, it should be acknowledged that there are tremendous opportunities for RNA-editing-based therapies to treat human diseases. It points out common downstream effectors of multiple editases, offering therapeutic targets that are more specifically linked to diseases. View all This reaction takes place in the 'nucleus'. This reaction takes place in the 'nucleus' Cho et al. R-HSA Reactome It is predicted that the target RNA could form secondary structures including stem-loop confirmation prior to the formation of editosome Maris et al.
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