P3‐012: Circular RNA (circRNA‐7; ciRS‐7) impacts microrna‐7 trafficking and downregulates the ubiquitin‐conjugating enzyme E2A (UBE2A) in sporadic Alzheimer's disease (AD) brain
Bibliographic record
Abstract
Circular RNAs (circRNAs) are a naturally occurring, unusually structured family of small, noncoding single-stranded RNAs (ssRNAs) highly expressed in the transcriptome of the human CNS. Traditional methodologies used for RNA detection and speciation studies, requiring a free 5′ or 3′ ribonucleotide terminus, may have significantly underestimated circRNA abundance and importance in regulating gene expression in CNS tissues. The circular nature of circRNAs makes them very stable and intrinsically resistant to ribonucleolytic enzyme attack. Specific ssRNAs such as the evolutionary ancient homo sapien microRNA-7 (hsa-miRNA-7; chr 9q21.32; ∼23 nt; http://www.mirbase.org/cgi-bin/mirnaentry.pl?acc= MI00 00263; a known, important post-transcriptional regulator of ubiquitination and phagocytosis), are not only very abundant in the human CNS, but are also associated with a circRNA for miRNA-7 (ciRS-7) containing anti-miRNA-7 sequences in the same tissues. Human brain and retinal ciRS-7 contains about ∼70 tandem anti-miRNA-7 sequences; ciRS-7 (∼1400 nt) thereby acts as a kind of endogenous, competing, anti-complementary miRNA “sponge” to adsorb, and hence quench, normal miRNA-7 function. Using RNA sequencing, DNA arrays, miRNA arrays, enhanced Northern blot hybridization and the circularity-sensitive 3′-5′ exoribonuclease probe RNaseR we provide here initial evidence of a mis-regulated ciRS-7-miRNA-7 system in sporadic Alzheimer's disease (AD) brain. Deficits in ciRS-7, and ciRS-7 “sponging activities” might be expected to increase ambient miRNA-7 levels in AD-affected brain cells, as is observed, and this appears to ultimately contribute to the down-regulation of selective miRNA-7-sensitive messenger RNA (mRNA) targets. The presence of excessive miRNA-7, likely due to a deficiency in ciRS-7 “sponging” effects, was shown to down-regulate AD-relevant targets, such as, the ubiquitin conjugating enzyme (UBE2A; miRNA-7-UBE2A mRNA energy of association, EA = −22.86 kcal/mol). UBE2A, a catalytic protease essential in the proteasome-mediated clearance of amyloid beta (Aβ) peptides was found to be significantly depleted in AD hippocampal CA1 and the superior temporal gyrus (Brodmann Area 22) compared to age-matched controls. These highly novel circRNA-miRNA-mRNA regulatory systems appear to represent another important layer of epigenetic control over transcriptional regulation and gene expression in the human brain and retina.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| 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 | 0.001 | 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".