Enhancing RNA base editing on mammalian transcripts with small nuclear RNAs.
Aaron A Smargon, Deepak Pant, Trent A Gomberg, Christian Fagre, Sofia Glynne, Johnathan Nguyen, Jack T Naritomi, Wendy V Gilbert, Gene W Yeo
Nature chemical biology · 2025
Abstract
Endogenous uridine-rich small nuclear RNAs (U snRNAs) form RNA-protein complexes to process eukaryotic pre-mRNA into mRNA. Previous studies have demonstrated programmable U snRNA guide-targeted exon inclusion and exclusion. Here we investigated whether snRNAs can also enhance RNA base editing over state-of-the-art RNA-targeting technologies in human cells. Compared with adenosine deaminase acting on RNA (ADAR)-recruiting circular RNAs, we find that guided A>I snRNAs consistently increase adenosine-to-inosine editing for higher exon count genes, perturb substantially fewer off-target genes and localize more persistently to the nucleus where ADAR is expressed. A>I snRNAs also more efficiently edit long noncoding RNAs and pre-mRNA 3' splice sites to promote splicing changes. Lastly, snRNA-H/ACA box snoRNA fusions (U>Ψ snRNAs) increase targeted RNA pseudouridylation without DKC1 overexpression, facilitating improved CFTR rescue from nonsense-mediated mRNA decay in a cystic fibrosis human bronchial epithelial cell model. Our results advance the endogenous protein-mediated RNA base editing toolbox and RNA-targeting technologies to treat genetic diseases.
Linked datasets 1
Enhancing RNA base editing on mammalian transcripts with small nuclear RNAs
Homo sapiens
20 data files
| File | Type | Size |
|---|---|---|
| DMD_cad_rep1_S10_L001_R1_001.fastq.gz | RNA-Seq | 2.2 GB |
| DMD_cad_rep3_S11_L001_R1_001.fastq.gz | RNA-Seq | 2.3 GB |
| DMD_U7_rep2_S12_L001_R1_001.fastq.gz | RNA-Seq | 2.5 GB |
| DMD_U7_rep3_S13_L001_R1_001.fastq.gz | RNA-Seq | 2.5 GB |
| pUC19_rep1_S32_L001_R1_001.fastq.gz | RNA-Seq | 2.3 GB |
| pUC19_rep2_S33_L001_R1_001.fastq.gz | RNA-Seq | 2.5 GB |
| RAB7A_cad_rep1_S34_L001_R1_001.fastq.gz | RNA-Seq | 2.4 GB |
| RAB7A_cad_rep2_S35_L001_R1_001.fastq.gz | RNA-Seq | 2.5 GB |
| RAB7A_U7_rep2_S36_L001_R1_001.fastq.gz | RNA-Seq | 2.3 GB |
| RAB7A_U7_rep3_S37_L001_R1_001.fastq.gz | RNA-Seq | 2.6 GB |
| SRR33284744_GSM8947646 | RNA-Seq | 2.6 GB |
| SRR33284745_GSM8947645 | RNA-Seq | 2.3 GB |
| SRR33284746_GSM8947644 | RNA-Seq | 2.5 GB |
| SRR33284747_GSM8947643 | RNA-Seq | 2.4 GB |
| SRR33284748_GSM8947642 | RNA-Seq | 2.5 GB |
| SRR33284749_GSM8947641 | RNA-Seq | 2.5 GB |
| SRR33284750_GSM8947640 | RNA-Seq | 2.3 GB |
| SRR33284751_GSM8947639 | RNA-Seq | 2.2 GB |
| SRR33284752_GSM8947638 | RNA-Seq | 2.5 GB |
| SRR33284753_GSM8947637 | RNA-Seq | 2.3 GB |
Potentially related datasets 1
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
Analysis pipelines 1
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE295421 RNA-seq Data Processing geo_data_processing | RNA-seq | 3 | GSE295421 |