Late-breaking abstract: The bromodomain-containing protein 4: The epigenetic origin of the oncogenic signature in pulmonary hypertension
Bibliographic record
Abstract
Background: As in cancer, pulmonary arterial hypertension (PAH) is associated with sustained DNA damage accounting for a PARP-1-dependent downregulation of miR-204. By an unknown mechanism, miR-204 promotes the expression of several oncogenes implicated in PAH including Survivin, Bcl-2, Pim-1 and c-Myc. Once activated, by affecting the mitochondrial function through the transcription factor NFAT, they contribute to the pro-proliferative and anti-apoptotic phenotype of PAH-pulmonary arterial smooth muscle cells (PASMC). In cancer, studies demonstrated that the epigenetic reader Bromodomain-containing protein 4 (BRD4) increases transcription of multiple oncogenes sustaining cell proliferation. Interestingly, BRD4 is upregulated by DNA damage and is a predicted target of miR-204. We hypothesized that the PARP-1/miR-204-dependent upregulation of BRD4 triggers the oncogenes-dependent pro-proliferative and anti-apoptotic phenotype seen in PAH-PASMC. Method/Results: BRD4 is upregulated in lungs, distal PAs and PASMC of PAH patients compared to healthy donors. This increase is miR-204 dependent, as miR-204 upregulation in PAH-PASMC decreases BRD4. BRD4 activation induces Bcl2, Survivin, c-Myc and Pim1 expression, leading to mitochondrial hyperpolarization (TMRM) and NFAT activation in PAH-PASMC, all of which were reversed upon molecular (siRNA) and pharmacological (JQ1 and I-BET) BRD4 inhibition. Finally, BRD4 inhibition reverses PAH-PASMC proliferation (Ki67) and resistance to apoptosis (TUNEL). Conclusion: Our study suggests an important role for BRD4 in pulmonary hypertension and opens the door to new avenues of investigation and proposes BRD4 as putative treatment for PAH.
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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 | 0.000 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.012 | 0.002 |
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".