Messenger RNA (mRNA) carries genetic instructions from DNA in the cell nucleus to the protein-building machinery in the cytoplasm. While the amount of mRNA often reflects how much protein a cell can make, not all mRNA molecules remain stable long enough to complete their task. This instability may help explain how certain genetic variants influence disease risk, according to researchers at the University of California Los Angeles.

The team, led by doctoral student Elaine Huang and integrative biology professor Xinshu Xiao, developed a software tool called RNAtracker that distinguishes whether a gene is regulated by changes in mRNA production or mRNA decay. The method was described in Nature Genetics in a study published on September 4.

Although the production of mRNA has been widely studied, less is known about the role of mRNA degradation. Every mRNA molecule is eventually broken down, but the rate at which this happens can vary significantly. This process affects how much protein is ultimately produced, and may play a role in various diseases.

Messenger RNA (mRNA)

A type of RNA that carries genetic instructions from DNA in the cell’s nucleus to ribosomes in the cytoplasm, where proteins are made.

Genetic variant

A change or mutation in DNA sequence that can alter gene function.

Tool identifies mutation-driven changes in mRNA decay

RNAtracker was tested on a dataset of 16 human cell lines in which newly synthesized mRNA molecules had been chemically tagged. By tracking the decay of these molecules over time, the researchers identified genes whose stability changed in the presence of specific genetic variants.

Many of the genes influenced by these stability-altering mutations were linked to the innate immune system, which responds rapidly to infections. This suggests that genetic variants affecting mRNA stability may influence immune activity and inflammation.

In addition, several of the variants associated with unstable mRNA had already been linked to autoimmune diseases in previous genome-wide association studies. These conditions included lupus, diabetes mellitus, multiple sclerosis and allergic rhinitis.

mRNA stability

Refers to how long an mRNA molecule remains intact before being degraded.

Implications for understanding disease mechanisms

The findings suggest that the stability of mRNA molecules – not just their production – may be a critical factor in gene regulation and disease susceptibility. For researchers exploring genetic causes of complex diseases, distinguishing between these two mechanisms could help clarify the biological impact of specific variants.

“Every mRNA has to die in the end. It’s produced, it does its job, and then it’s destroyed. But 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.”

Dr. Xinshu Xiao.

The authors noted that while previous work focused on how much mRNA is made, their study draws attention to how long it lasts. This shift in focus may expand the range of targets for therapeutic intervention.

The data used in the study were generated by the ENCODE project, a large-scale initiative supported by the National Institutes of Health (NIH) that makes genomic datasets publicly accessible. The research received direct funding from NIH as well.

Reference: Huang E, Fu T, Zhang L, et al. Genetic variants affecting RNA stability influence complex traits and disease risk. Nature Genetics. 2025. doi: 10.1038/s41588-025-02326-8

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