Abstract 375: Regulation of the Long Non-coding RNA Transcriptome in Endothelial Cells in Response to Shear Stress
Bibliographic record
Abstract
Fluid shear stress, the frictional force exerted by blood flow, is a key modulator of the expression of endothelial cell (EC) protein-coding genes. In the absence of laminar (healthy) blood flow, EC gene expression becomes dysfunctional (e.g. reduced eNOS expression) which can predispose the vessel to atherosclerosis. However, the effects of shear stress on the non-coding transcriptome are not fully defined, particularly long non-coding RNAs (lncRNAs), which are transcripts >200 nts that do not encode proteins yet regulate gene expression via diverse epigenetic mechanisms. Previously, we have identified an EC-enriched lncRNA, termed STEEL , that is induced by the absence of laminar flow to promote angiogenesis and vessel maturation in vivo . The objective of this work is to comprehensively study the effects of shear stress on EC lncRNAs to uncover novel genes that contribute to vascular homeostasis. Five independent HUVEC lines were subjected to either static (no flow) or laminar flow conditions (10 dynes/cm 2 ) for 48 hrs using a parallel plate flow chamber. RNA was isolated and analyzed using a custom human lncRNA microarray to profile 30,586 lncRNAs. In brief, 75 (0.25%) and 47 (0.15%) lncRNAs were up-regulated or down-regulated respectively (≥4 fold vs. static, p<.05). Using qRT-PCR, the top 3 highly induced and repressed lncRNAs exhibited responses to flow ranging from 10-1500 fold. HUVECs overexpressing KLF2, a transcription factor activated by laminar flow in ECs, revealed a subset of flow-induced lncRNAs to be regulated by this pathway including one which we termed NIMBUS . The NIMBUS locus is located adjacent to MEF2A, an upstream regulator of KLF2 expression in response to laminar flow. Knockdown of MEF2A using siRNA in either flow or KLF2-overexpressing ECs reduced the expression of NIMBUS confirming that NIMBUS is also regulated by MEF2A. Microarray analysis of NIMBUS KD via siRNA in KLF2-overexpressing ECs revealed several NIMBUS target genes important for vascular homeostasis including eNOS, DKK2, and CNP. These findings demonstrate that lncRNAs are novel regulators in the EC response to shear stress and represent additional gene targets for improved therapeutic and diagnostic modalities for cardiovascular diseases.
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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) | 0.002 | 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".