How mRNA Stability Influences Immune Diseases

DNA serves as an intricate instruction manual within every human cell, containing the directions for constructing proteins essential for body functions. Genes provide these instructions, but they must travel from the nucleus to the cytoplasm, where proteins are synthesized. Messenger RNA (mRNA) plays a critical role in this process by transferring the instructions from DNA to the protein-making machinery. Typically, an increase in mRNA levels leads to higher protein production, unless the mRNA molecules are unstable and break down before their task concludes.

According to Xinshu Xiao, senior author on a new study published in Nature Genetics, while research has traditionally prioritized the formation of mRNA, less attention has been paid to its degradation, which is equally important. Both the amount and stability of mRNA can be influenced by genetic variants—mutations in DNA that can alter the volume of protein a cell manufactures and ultimately impact disease risk. Distinguishing whether such variants affect mRNA creation or longevity has posed significant hurdles for scientists

To address this challenge, Xiao and collaborators from UCLA introduced RNAtracker, a freely accessible computational tool that enables researchers to determine if a gene is regulated through changes in mRNA production or stability. By applying RNAtracker to data from 16 human cell lines—where newly synthesized mRNAs were labeled and monitored—the researchers identified genes with variable stability caused by specific mutations. Notably, many of these genes play roles in the body’s immune defenses, particularly within the innate immune system.

Further analysis revealed that several genetic variants tied to unstable mRNA are already linked with autoimmune disorders, as documented in large-scale genetic studies. Xiao remarked, “One insight from this project is that some disease-associated variants may be acting through effects on mRNA stability.” By employing additional modeling, the team connected expression levels of these genes regulated by mRNA stability to conditions such as allergic rhinitis, lupus, diabetes mellitus, and multiple sclerosis. This research highlights mRNA stability as a mechanism that may play a vital role in numerous immune-related diseases, a concept previously underappreciated by the scientific community.

As first author Elaine Huang explained, “For drug developers or researchers working on treatments, you can’t target what you don’t know is important. We are trying to bring attention to genetic variants that affect mRNA stability, which hasn’t gotten the spotlight it deserves.”