Transcription Study Identifies Links to Neurodegenerative Disease

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Transcription is the process of copying a strand of DNA into a corresponding RNA molecule. Although transcription is a fundamental process, differences in accuracy exist between cell types and genomic regions. A new study recently released by a group of multi-institutional researchers investigated transcription error rates along with the causal molecular mechanisms.

Errors during transcription of messenger RNA can cause the resulting transcribed proteins to be truncated or lose properties required for their function. Other species of RNA, like non-coding RNA suffering from transcription errors, may also lose their crucial functions, which are often important for regulatory elements of the cell. The mechanisms related to these errors remained largely unsolved and prompted the initiation of this work.

The study began by analyzing the transcriptome of H1 human embryonic stem cells to determine the error rates of transcription in humans. Using a circle-sequencing method, the researchers inspected high-fidelity sequences from isolated transcripts. This sequencing technique helped identify roughly 100,000 errors spread across the major RNA species in humans.

In addition, the results show that different error rates are present in different RNA species, which suggests that human cells can prioritize the fidelity of certain RNAs. To further understand this process, the researchers cross-referenced the discovered errors with genetic and epigenetic features. Other factors such as gene length, complexity, and nucleotide composition were shown to play an influence on transcription errors. The different types of RNA polymerases, epigenetic markers, and speed of transcription were also involved in producing errors during transcription.

Further investigations were completed on DNA repair proteins necessary to fix these errors. One notable protein, BRAC1, was shown to be vital in improving transcriptional fidelity. BRAC1 is also well known for its heavily studied mutations linked to breast and ovarian cancer.

The final segment of the study involved using a developed mouse model to identify the impact of transcription errors on protein misfolding and find the most susceptible cell types. When analyzing the distribution of these transcription errors across multiple tissues, they discovered that the errors occurred preferentially in neurons. Two critical regions of the brain, CA1 and dentate gyrus, were especially prone to transcriptional mutagenesis or DNA alterations.

These results support the belief that errors during transcription, especially in neurons, are crucial in the progression of neurological diseases like Alzheimer’s. Researchers from the study say their next steps will be establishing the connection between these errors and cell health.

More information about the original study published in PNAS can be found here.