eLife Assessment: PRMT1-SFPQ regulates intron retention to control matrix gene expression during craniofacial development
Bibliographic record
Abstract
Spliceosomopathies, which are a group of disorders caused by defects in the splicing machinery, frequently affect the craniofacial skeleton and limb, but the molecular mechanism underlying this tissue-specific sensitivity remains unclear. Splicing factors and small nuclear ribonucleoproteins (snRNPs) are core components of splicing machinery, and splicing factors are further controlled by post-translational modifications, among which arginine methylation is one of the most frequent modifications. To determine the splicing mechanisms in cranial neural crest cells (CNCCs), which give rise to the majority of the craniofacial skeleton, we focused on upstream regulators for splicing proteins responsible for arginine methylation, protein arginine methyltransferases (PRMT). These enzymes catalyze arginine methylation of splicing factors to modify splicing factor expression and activity, influencing the splicing product. PRMT1 is the highest expressing enzyme of the PRMT family in CNCCs and its role in craniofacial development is evident based on our earlier investigation, where CNCC-specific Prmt1 deletion caused cleft palate and mandibular hypoplasia. In the present study, we uncover the roles of PRMT1 in CNCCs in the regulation of intron retention, a type of alternative splicing where introns are retained in the mature mRNA sequence. Mandibular primordium of Prmt1-deficient embryos demonstrated an increase in the percentage of intron-retaining mRNA of matrix genes, which triggered NMD, causing a reduction in matrix transcript expression. We further identified SFPQ as a substrate of PRMT1 that depends on PRMT1 for arginine methylation and protein expression in the developing craniofacial structures. Depletion of SFPQ in CNCCs phenocopied PRMT1 deletion in that matrix, Wnt signaling components and neuronal gene transcripts contained higher IR and exhibited lower expression. We further recognized gene length as a common feature among SFPQ-regulated genes in CNCCs. Altogether, these findings demonstrate that the PRMT1-SFPQ pathway modulates matrix Wnt signaling components and neuronal gene expression via intron retention in CNCCs during craniofacial development.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.028 | 0.016 |
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 source (direct Gemma or distilled Codex), 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".