The role of PRMT5 in regulating the expression of circular intronic RNAs
Bibliographic record
Abstract
The protein arginine methyltransferase 5 (PRMT5) is frequently overexpressed in human cancer whose elevated activity is associated with poor clinical prognosis.Pharmacologic inhibitors of PRMT5 are actively being pursued as a cancer treatment.At the molecular level, PRMT5 plays a critical role in pre-mRNA splicing by catalyzing the symmetrical arginine dimethylation of the Sm proteins; thus, promoting the maturation of small nuclear ribonucleoproteins (snRNPs).Disruption of PRMT5 is known to induce splicing defects, such as exon skipping and intron retention.Herein, we identify a new role of PRMT5 in regulating pre-mRNA splicing by modulating the expression of circular intronic RNAs (ciRNAs).ciRNAs are intronic lariats generated after splicing that confer resistance to degradation and remain stable in the nucleus.We demonstrate that PRMT5 depletion in U2OS cells results in the accumulation of several ciRNAs, such as ciPLK1 and ciANKRD52, as measured by qRT-PCR using convergent and divergent primers.To verify the circularity of the ciRNA transcripts, we show that first, they are not efficiently reverse-transcribed using oligo-dT primers and second, they are resistant to RNaseR degradation which specifically digests linear but not circular RNA.To explore their cellular significance, we report that the transient transfection of in vitro generated circular RNAs and 2'-5' branched RNA oligomers into HEK-T293 cells stimulates innate immunity gene expression.Lastly, we find that knockdown of ciPLK1, which is derived from the first intron of the PLK1 gene, is sufficient to rescue the reduced expression of the parental mRNA upon PRMT5 depletion.In conclusion, our findings demonstrate that PRMT5 is required for the proper regulation of the levels of ciRNAs in mammalian cells and suggest that the ciRNAs identified can negatively modulate the expression of their parental mRNAs in cis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".