Abstract 16338: Dna Hypomethylation in Long Non-coding Rna Promoter During Calcific Aortic Valve Stenosis: Implication for the Notch Pathway
Bibliographic record
Abstract
Introduction:Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease. Transdifferentiation of valve interstitial cells of the aortic valve (VICs) into osteogenic cells is an important process in the pathology. However, the molecular mechanisms involved in gene expression during osteogenic transition are still poorly understood. Hypothesis:Long non-coding RNAs (lncRNAs) regulate gene expression pattern and may be involved in the osteogenic transdifferentiation during the development of the CAVS. Methods:Transcriptomic by RNA sequencing (RNA-seq) and DNA genome-wide methylation studies were performed in human aortic valves. In addition, the role of a lncRNA on the mineralization was explored and the molecular mechanisms by which it promotes osteogenic transdifferentiation was documented. Results:Transcriptomic profiling of CAVS and control valves revealed that a lncRNA was highly expressed in mineralized valves. The CpG islands in the promoter region of the gene coding this lncRNA were hypomethylated (n=23). These data were confirmed by q-PCR (n=152), fluorescence in situ hybridization (FISH) and pyrosequencing (n=60). Methylation status of the lncRNA promoter was inversely related to expression level and in isolated VICs a treatment with 5-aza-2’-deoxycytidine, which causes DNA demethylation, increased the expression of lncRNA by 2,5-fold. Knockdown or overexpression experiments showed that lncRNA play an important role in the osteogenic transdifferentiation via the Notch1 pathway. Promoter studies coupled with luciferase and chromatin immunoprecipitation (ChIP) revealed that this lncRNA interferes with the activity of Notch1 by physically interacting with the promoter. LncRNA-induced mineralization of VICs was rescued by a co-transfection of a vector encoding for the Notch intracellular domain (NICD). Conclusions:During CAVS the hypomethylation in the promoter region promotes the overexpression of a lncRNA. This lncRNA promotes the dysfunction of the Notch signaling pathway and induces the osteogenic transdifferentiation of VICs.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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 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".