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Researchers at the University of California Los Angeles (UCLA) have identified thousands of genetic variants that affect the stability of messenger RNA (mRNA) transcripts to regulate gene expression, many of them linked to autoimmune conditions such as lupus or multiple sclerosis. Their findings, published today in Nature Genetics, showcase the importance of an often overlooked mechanism of disease.
“Most research has focused on how mRNA is made. Much less attention has been paid towards how fast it’s degraded, and that’s just as important,” says Xinshu Xiao, PhD, professor of integrative biology and physiology at UCLA and senior author of the study. “This work highlights RNA stability as a critical, yet understudied mechanism linking genetic variation and disease.”
Gene expression is an intricate process orchestrated by complex molecular pathways. Research into genetic drivers of disease often focuses on how gene variants can alter gene expression by regulating transcription levels, which directly affects the amount of mRNA transcripts the cell produces. However, gene expression can also be regulated through mRNA stability, which determines how long mRNA molecules survive and therefore influences how much of the encoded protein gets translated and produced in the cell.
A major limitation in this field has been the lack of techniques to study which genetic variants affect mRNA stability to regulate expression. To overcome this, Xiao and colleagues developed a computational tool called RNAtracker that can classify gene variants according to whether they affect mRNA transcription or mRNA stability.
Using a technique known as metabolic pulse-chase labeling, newly made mRNA molecules were chemically labelled and tracked over time. RNAtracker was then used to screen for gene expression changes across 11 human cell lines from a publicly available dataset, identifying more than 5,000 gene variants that affect mRNA stability among 665 genes.
“One insight from this project is that some disease-associated variants may be acting through effects on mRNA stability,” said Xiao. Results showed that many of the genes whose expression is regulated through mRNA stability are involved in immune system functions, particularly in the innate immune system. Several of the genetic variants identified in the study were also found to be associated with autoimmune disease, as described in previous large-scale genetic studies. These genes were linked to a wide range of diseases including allergic rhinitis, lupus, diabetes mellitus, and multiple sclerosis.
Taken together, these results highlight the important role that gene expression mechanisms mediated by mRNA stability can play in disease, particularly in immune-related conditions. Xiao and colleagues see immense potential in this discovery to provide a stepping stone for further research to uncover new therapeutic strategies that target this long overlooked regulatory mechanism.
“Basic research like ours shifts the paradigm of what people focus on,” said Elaine Huang, bioinformatics PhD candidate at UCLA and first author of the study. “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.”