Three conserved domains in the 3’UTR region of αENaC mRNA modulates the stability of the transcript in alveolar epithelial cells (716.1)
Bibliographic record
Abstract
The epithelial sodium channel (ENaC) plays an important role in the alveolar epithelium by mediating Na + reabsorption, an essential process for resolution of pulmonary edema in acute respiratory distress syndrome (ARDS). Several proinflammatory conditions such as TNF‐α leads to a reduction of ENaC expression and activity that contributes to development of ARDS. To study how pro‐inflammatory conditions could modulate αENaC mRNA stability, we developped a Tet‐Off model that allows the specific inhibition of αENaC mRNA expression in presence of doxycycline. Using this model, we found that the half‐life (T 1/2 ) for the transcript was about 1 hr. TNF‐α, a proinflammatory cytokine found in broncho‐alveolar lavage of ARDS patients, decreased T 1/2 to 15 min, suggesting that destabilisation of αENaC transcript plays an important role in downregulation of ENaC expression in pro‐inflammatory conditions. The 3’ untranslated region (3’UTR) of a mRNA plays an important role in modulating mRNA stability. αENaC mRNA 3’UTR is very long (~30% of the transcript). Using a bioinformatic approach, we could define three domains (D1, D2, D3) able to form secondary structures that were highly conserved in different species. Alveolar epithelial cells were co‐transfected with 3’UTR deletion mutants inserted in pTRE‐tight vector along with the Tet‐Off vector. Deletion of the distal part of 3’UTR (D3) leaded to stabilization of the transcript with a T 1/2 of 2.6 hrs. A longer deletion to remove also D2 showed a T 1/2 of 4.6 hrs, while deletion of D1 decreased the half‐life to 0.5 hr. These results showed that the conserved domains have stabilizing (D1) and destabilizing (D2, D3) properties on αENaC mRNA expression. The hairpin structure of these domains could recruit RNA‐binding proteins responsible for modulation of αENaC mRNA stability. Altogether, our results suggest that modulation of αENaC mRNA stability via its 3’UTR could play an important role in regulation of ENaC expression during pro‐inflammatory conditions. Grant Funding Source : Supported by FRSQ, CFC and CIHR.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".