fafter transcription, RNA molecules can undergo modifications. For example, nucleotides can be inserted, deleted or changed. One of the most common operations, which new research shows plays an important role in the development of inflammatory disease, is the transformation of the nucleotide adenosine into inosine within a double-stranded RNA. A study published on Wednesday (Aug. 3) in Nature reveals that genetic variants that dampen this particular modification are associated with an increased risk of autoimmune diseases and immune-mediated inflammatory conditions such as psoriasis, inflammatory bowel disease and type 1 diabetes. The authors propose that a sensor protein likely mistakes these less processed RNAs for foreign molecules, triggering an inflammatory response.
“I think it’s a really big 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 rather 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 divide.
The transformation of adenosine into inosine is catalyzed by adenosine deaminase which acts on RNA enzymes (ADAR). By binding to a double-stranded RNA and converting the selected nucleotide, the enzyme changes the base pairs in the RNA, changing its conformation as well. In 2015 scientists demonstrated how essential this process is for health: mutated mice with ADAR deficient died before birth. However, the fatal outcome was prevented by removing another protein, MDA5, a watchful 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 attracting the attention of MDA5.
Subsequent research found that mutations that affect ADAR processing capacity or increase the sensitivity of the MDA5 sensor can lead to rare autoimmune diseases, such as Aicardi-Goutières syndrome and others neurological disorders, in people. However, these mutations are “very rare,” says Stanford University geneticist Jin Billy Lie, one of the researchers behind the new study and the 2015 paper. But he says he and his colleagues wondered, “What happens to many of these double-stranded RNAs that may not be processed properly?” – could processing deficiencies not attributable to these known protein mutations be the cause of more common diseases?
To test their hypothesis, Li and his colleagues first identified genetic variants that affect RNA editing. To do this, they analyzed genomic and genetic expression data from postmortem samples of various tissues taken from 838 human donors whose information is stored in the Catalog Genotype-Tissue Expression (GTEx). Computer analyzes 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 with genome-wide association studies with an increased risk of certain diseases.
This showed that the genetic variants associated with impaired RNA editing are common among variants previously associated with multiple autoimmune or immune-related disorders, such as lupus, multiple sclerosis and coronary artery disease. The variants that affect RNA editing appeared to have stronger associations with those diseases compared to variants that affect gene expression or splicing, which are also linked to immune-related diseases. In addition, 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.
The authors’ main achievement was to establish a link between RNA editing variants and immune-related and common inflammatory diseases, says Yi Xing, a computer biologist at the Children’s Hospital of Philadelphia who did not participate in this study. But beyond that, they offered “a really interesting mechanism” to explain such a connection, he says.
O’Connell adds that these findings could have major clinical implications in the future. Now that we know that RNA editing is important, she says, it probably won’t be that difficult to develop clinical tests for RNA editing levels. Understanding someone’s vulnerability based on such information can help clinicians prevent or control inflammation, she notes.
Li, who co-founded the biotech company AIRNA Bio, a consultant to Risen Pharma, and has filed a patent for a method to predict double-stranded RNA loading, says these findings suggest that for “a subset of patients, inflammation may be driven.” due to the insufficient processing of many double-stranded RNAs.” He adds that he and his colleagues are now trying to determine whether it would be possible to “silence this double-stranded RNA detection pathway” and, as a result, treat these common diseases.