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Following transcription, RNA molecules can undergo modifications. For example, nucleotides may be inserted, deleted, or changed. One of the most common edits, which new research shows plays an important role in the onset of inflammatory disease, is the transformation of the nucleotide adenosine into inosine within a double-stranded RNA. A study published Wednesday (August 3) in Nature reveals that genetic variants that dampen this specific modification are associated with an increased risk of autoimmune and immune-mediated inflammatory disorders such as psoriasis, inflammatory bowel disease, and type 1 diabetes. The authors propose that a sensor protein likely mistakes these less-edited RNAs for foreign molecules, triggering an inflammatory response.
“I think it’s really a major breakthrough,” says Mary A. O’Connell, a molecular biologist at the Central European Institute of Technology at Masaryk University in the Czech Republic who did not participate in this study but has previously collaborated with some of the authors. She adds that she found it “really striking” how important RNA editing appears to be for inflammatory diseases, compared to gene expression or splicing.
The transformation of adenosine into inosine is catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes. By binding to a double-stranded RNA and converting the selected nucleotide, the enzyme alters the base pairings within the RNA, thereby also changing its conformation. In 2015, scientists demonstrated how essential this process is to health: mutant mice carrying a deficient ADAR died before birth. The fatal outcome, however, was prevented by deleting another protein, MDA5, a vigilant molecule that recognizes foreign invaders through their double-stranded RNA and triggers an inflammatory response. These previous findings revealed that ADAR-dependent RNA editing of adenosine into inosine is necessary to avoid drawing the attention of MDA5.
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Subsequent research found that mutations that affect the editing capacity of ADAR or increase the sensitivity of the MDA5 sensor can lead to rare autoimmune diseases, such as Aicardi-Goutières syndrome and other neurological conditions, in humans. These mutations, however, “are very rare,” says Stanford University geneticist Jin Billy Li, one of the researchers behind the new study as well as the 2015 paper. But he says he and his colleagues wondered, “what happens to many of these double-stranded RNAs that may not be properly edited?”—could editing deficiencies not due to these known protein mutations be at fault in more common diseases?
To test their hypothesis, Li and his colleagues first identified genetic variants that affect RNA editing. To do so, they analyzed genomic and genetic expression data of postmortem samples of various tissues taken from 838 human donors whose information is stored in the Genotype-Tissue Expression (GTEx) catalog. Computational analyses of these variants suggest that they affect the binding strength between ADAR and the RNAs. Next, the team assessed whether these variants were significantly abundant in regions of the genome previously associated in genome-wide association studies with an increased risk for certain diseases.
Doing so revealed that the genetic variants linked to reduced RNA editing were common among variants previously associated with multiple autoimmune or immune-related conditions, such as lupus, multiple sclerosis, and coronary artery disease. The variants affecting RNA editing appeared to have stronger associations with those diseases compared to variants affecting gene expression or splicing, which have also been linked to immune-related diseases. Moreover, the effect of the RNA editing variants was clearly directional: They were associated with reduced, not increased, editing levels, reinforcing the idea that a lack of ADAR-mediated editing is detrimental to one’s health.
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The main achievement of the authors was to establish a link between RNA editing variants and immune-related and common inflammatory diseases, says Yi Xing, a computational biologist at the Children’s Hospital of Philadelphia who did not participate in this study. But in addition to that, they provided “a really interesting mechanism” to explain such a link, he says.
O’Connell adds that these findings may have major clinical implications in the future. If we now know that RNA editing is important, she says, it will likely not be so difficult to develop clinical tests for RNA editing levels. Understanding the vulnerability of someone based on such information may help clinicians to prevent or control inflammation, she notes.
Li, who is a cofounder of the biotech company AIRNA Bio, a consultant for Risen Pharma, and has filed a patent for a method to predict double-stranded RNA burden, says these findings suggest that for “a subset of patients, the inflammation might be driven by the insufficient editing of many double-stranded RNAs.” He adds that he and his colleagues are now trying to determine whether it would be possible “to dampen this double-stranded RNA sensing pathway” and, as a result, treat these common diseases.