Recent research from the University of Chicago reveals that alternative splicing significantly influences gene expression regulation, rather than just contributing to protein diversity.

The research team, led by Yang Li, analyzed genomic data and found that cells produce three times as many unproductive transcripts—RNA molecules with errors—compared to steady-state RNA.

On average, about 15% of RNA transcripts are degraded by a cellular process known as nonsense-mediated decay (NMD), a figure that increases to 50% for genes with low expression levels.

Li's team highlighted the efficiency of NMD, suggesting it allows cells to produce erroneous transcripts without significant selective pressure to minimize mistakes.

Li posits that cells may intentionally select certain transcripts for degradation to reduce gene expression, effectively silencing specific genes.

The study involved a genome-wide association study (GWAS) that linked genetic variations affecting unproductive splicing to differences in gene expression levels, particularly in complex diseases.

These findings suggest potential avenues for new treatments that could manipulate the alternative splicing-NMD process to either enhance or reduce gene expression.

The findings, published in Nature Genetics, emphasize that alternative splicing may have broader biological impacts than previously understood.

Existing drugs for conditions like spinal muscular atrophy already utilize the principle of manipulating splicing to restore proteins that are being suppressed.

The research was funded by the National Institutes of Health and involved contributions from multiple authors affiliated with the University of Chicago and the University of California, Davis.

Li concluded that the most critical role of alternative splicing may be in regulating gene expression rather than solely generating protein complexity.

Potential therapies may involve designing drugs that reduce unproductive splicing to enhance gene expression or increasing NMD to lower expression in cases such as cancer.