Circular RNA Profiling Identifies <i>circ5078</i> as a <i>BMPR2</i> -Derived Regulator of Endothelial Proliferation and Stress Responses
Bibliographic record
Abstract
BACKGROUND: The BMPR2 gene encodes the BMPR-II (bone morphogenetic protein receptor type-II) and is a known regulator of endothelial proliferation, apoptosis, and translational stress responses. While these effects are generally attributed to the actions of BMPR-II protein, we used circular RNA profiling to identify circ3218 and circ5078 as new BMPR2 -derived functional RNAs. METHODS: Circular RNAs were profiled by ultradeep RNA sequencing of human pulmonary artery endothelial cells. Novel BMPR2 -derived circular RNAs were assessed for their effects on endothelial proliferation, apoptosis, and translational stress responses in human pulmonary artery endothelial cells and endothelial cells from patients with pulmonary arterial hypertension with heterozygous loss-of-function BMPR2 mutations. circ5078 to linear BMPR2 mRNA ratios were quantified in cultured lymphocytes from patients with pulmonary arterial hypertension with BMPR2 mutations versus unaffected mutation carriers. RESULTS: Depletion of circ3218 enhanced human pulmonary artery endothelial cell apoptosis, whereas circ5078 silencing increased proliferation. Enhanced proliferation with circ5078 depletion was eliminated by cosilencing of circ5078 with either linear BMPR2 mRNA or the stress granule protein, Caprin-1, indicating a potential interdependence of BMPR2 transcripts in the regulation of endothelial function. Patients with pulmonary arterial hypertension with BMPR2 mutations exhibited increased circ5078 to linear BMPR2 mRNA ratios, alongside impaired stress responses in patient endothelial cells that were deficient in linear BMPR2 transcripts but not circ5078 . circ5078 depletion enhanced stress responses in human pulmonary artery endothelial cells and rescued stress granule formation in patient endothelial cells, independent of BMPR-II protein levels. Assessment of translational regulation by polysome profiling did not identify any impact of linear or circular BMPR2 transcript loss on global protein synthesis or stress-induced eIF2α (eukaryotic initiation factor 2α) phosphorylation but did identify the enhanced translational efficiency of select nuclear-encoded mitochondrial ribosome proteins with circ5078 depletion, offering a link between mitochondrial function and the circ5078 -deficient endothelial phenotype. CONCLUSIONS: The identification of circ3218 and circ5078 as novel BMPR2 -derived gene products reveals interdependent roles for coding and noncoding BMPR2 transcripts as regulators of endothelial function.
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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 | 0.000 | 0.000 |
| 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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".