The fidelity of transcription in human cells.
Claire ChungBert M VerheijenXinmin ZhangBiao HuangAeowynn CoakleyEric McGannEmily WadeOlivia Dinep-SchneiderJessica LaGoshMaria-Eleni AnagnostouStephen SimpsonKelley W ThomasMimi ErnstAllison RattrayMichael LynchMikhail KashlevBerenice A BenayounZhongwei LiJeffrey StrathernJean-Francois GoutMarc VermulstPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
To determine the error rate of transcription in human cells, we analyzed the transcriptome of H1 human embryonic stem cells with a circle-sequencing approach that allows for high-fidelity sequencing of the transcriptome. These experiments identified approximately 100,000 errors distributed over every major RNA species in human cells. Our results indicate that different RNA species display different error rates, suggesting that human cells prioritize the fidelity of some RNAs over others. Cross-referencing the errors that we detected with various genetic and epigenetic features of the human genome revealed that the in vivo error rate in human cells changes along the length of a transcript and is further modified by genetic context, repetitive elements, epigenetic markers, and the speed of transcription. Our experiments further suggest that BRCA1, a DNA repair protein implicated in breast cancer, has a previously unknown role in the suppression of transcription errors. Finally, we analyzed the distribution of transcription errors in multiple tissues of a new mouse model and found that they occur preferentially in neurons, compared to other cell types. These observations lend additional weight to the idea that transcription errors play a key role in the progression of various neurological disorders, including Alzheimer's disease.
Keyphrases
- single cell
- transcription factor
- dna repair
- gene expression
- rna seq
- genome wide
- patient safety
- adverse drug
- endothelial cells
- mouse model
- embryonic stem cells
- dna damage
- induced pluripotent stem cells
- emergency department
- body mass index
- spinal cord
- high frequency
- stem cells
- mesenchymal stem cells
- pluripotent stem cells
- cell therapy
- small molecule
- young adults
- spinal cord injury
- blood brain barrier