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Alternative splicing, a well-known genetic mechanism, plays an important role in expanding the diversity of proteins that can be generated from a single gene. This process, where different segments of genes are removed and the remaining pieces are reassembled, has long been recognized for its ability to produce various protein isoforms, adding to the complexity of biological systems. However, new research from the University of Chicago suggests that alternative splicing might play an even bigger role in regulating gene expression levels rather than just creating protein diversity.
Published recently in Nature Genetics, the study led by Yang Li, Benjamin Fair, and Carlos Buen Abad Najar delves into the extensive impact of alternative splicing on gene regulation. By analyzing large genomic datasets that span different stages of RNA transcription—from the initial transcription phase to the eventual degradation of RNA transcripts—the researchers observed a surprising prevalence of "unproductive" transcripts. These RNA molecules, which contain errors or unexpected configurations, are rapidly degraded by the cell's nonsense-mediated decay (NMD) pathway.
The team's analysis revealed that cells produce three times more unproductive transcripts than previously thought when considering steady-state, mature RNA. On average, about 15% of RNA transcripts are swiftly targeted for degradation by NMD, a figure that rises to 50% in genes with lower expression levels. "It already seems wasteful to degrade 15% of mRNA transcripts," said Li, an Associate Professor of Medicine and Human Genetics, "but no one would have thought that the cell is transcribing so much and getting rid of the errors immediately, seemingly without any purpose."
A Potentially Purposeful Process
The discovery raised questions about why cells would invest in producing such a significant amount of RNA only to discard it immediately. Li suggests that the efficiency of the NMD pathway allows cells to make these mistakes without consequence, as there is little selective pressure to reduce transcription errors. However, the team suspected that there might be an underlying purpose to this widespread phenomenon.
To explore this, the researchers conducted a genome-wide association study (GWAS) to compare gene expression levels across different cell lines. Their findings revealed genetic variations at loci known to influence unproductive splicing. These variations were just as often associated with differences in gene expression due to NMD as they were with variations in protein isoform production.
Li and his team propose that cells may sometimes deliberately select transcripts destined for NMD as a means of controlling gene expression. By destroying the nascent RNA before it is fully transcribed, the cell effectively silences the gene, preventing it from producing proteins that would carry out biological functions. "This shows that this mechanism must have some effect on expression because it is so widespread," Li explained.
Implications for Disease and Therapeutics
Further analysis revealed that many genetic variants linked to complex diseases are also associated with increased unproductive splicing and decreased gene expression. This finding suggests that a better understanding of the alternative splicing-NMD process could pave the way for novel therapeutic approaches. For instance, drug molecules could be designed to reduce unproductive splicing, thereby boosting gene expression. One existing drug for spinal muscular atrophy already leverages this strategy by restoring proteins that are otherwise shut off.
Conversely, enhancing the NMD process could be a strategy to decrease the expression of overactive genes, such as those involved in cancer.
"We think we can target a lot of genes because now we know how much this process is going on," Li noted. This research challenges the traditional view of alternative splicing as merely a mechanism for increasing protein complexity, suggesting that its primary function might be to control gene expression levels.
Publication Details
Fair, B., Buen Abad Najar, C.F., Zhao, J. et al. Global impact of unproductive splicing on human gene expression. Nat Genet (2024). https://doi.org/10.1038/s41588-024-01872-x
Published recently in Nature Genetics, the study led by Yang Li, Benjamin Fair, and Carlos Buen Abad Najar delves into the extensive impact of alternative splicing on gene regulation. By analyzing large genomic datasets that span different stages of RNA transcription—from the initial transcription phase to the eventual degradation of RNA transcripts—the researchers observed a surprising prevalence of "unproductive" transcripts. These RNA molecules, which contain errors or unexpected configurations, are rapidly degraded by the cell's nonsense-mediated decay (NMD) pathway.
The team's analysis revealed that cells produce three times more unproductive transcripts than previously thought when considering steady-state, mature RNA. On average, about 15% of RNA transcripts are swiftly targeted for degradation by NMD, a figure that rises to 50% in genes with lower expression levels. "It already seems wasteful to degrade 15% of mRNA transcripts," said Li, an Associate Professor of Medicine and Human Genetics, "but no one would have thought that the cell is transcribing so much and getting rid of the errors immediately, seemingly without any purpose."
A Potentially Purposeful Process
The discovery raised questions about why cells would invest in producing such a significant amount of RNA only to discard it immediately. Li suggests that the efficiency of the NMD pathway allows cells to make these mistakes without consequence, as there is little selective pressure to reduce transcription errors. However, the team suspected that there might be an underlying purpose to this widespread phenomenon.
To explore this, the researchers conducted a genome-wide association study (GWAS) to compare gene expression levels across different cell lines. Their findings revealed genetic variations at loci known to influence unproductive splicing. These variations were just as often associated with differences in gene expression due to NMD as they were with variations in protein isoform production.
Li and his team propose that cells may sometimes deliberately select transcripts destined for NMD as a means of controlling gene expression. By destroying the nascent RNA before it is fully transcribed, the cell effectively silences the gene, preventing it from producing proteins that would carry out biological functions. "This shows that this mechanism must have some effect on expression because it is so widespread," Li explained.
Implications for Disease and Therapeutics
Further analysis revealed that many genetic variants linked to complex diseases are also associated with increased unproductive splicing and decreased gene expression. This finding suggests that a better understanding of the alternative splicing-NMD process could pave the way for novel therapeutic approaches. For instance, drug molecules could be designed to reduce unproductive splicing, thereby boosting gene expression. One existing drug for spinal muscular atrophy already leverages this strategy by restoring proteins that are otherwise shut off.
Conversely, enhancing the NMD process could be a strategy to decrease the expression of overactive genes, such as those involved in cancer.
"We think we can target a lot of genes because now we know how much this process is going on," Li noted. This research challenges the traditional view of alternative splicing as merely a mechanism for increasing protein complexity, suggesting that its primary function might be to control gene expression levels.
Publication Details
Fair, B., Buen Abad Najar, C.F., Zhao, J. et al. Global impact of unproductive splicing on human gene expression. Nat Genet (2024). https://doi.org/10.1038/s41588-024-01872-x