P089 Long ncRNA Landscape in the Rectum of Treatment Naïve Early Onset Ulcerative Colitis Highlights Association with Severity and Early and Late Disease Outcome, with Potential Role in Epithelial Metabolic Functions
Bibliographic record
Abstract
Abstract Background Long non-coding RNAs (lncRNAs) are tissue-specific and regulate cellular functions. We previously reported a dramatic inhibition of epithelial metabolic mitochondrial functions in mucosal biopsies from the UC PROTECT cohort. We aimed to define lncRNAs that are dysregulated in UC, linked with attenuated epithelial metabolic functions, and associated with worse outcome. Methods Transcriptomics of pre-treatment rectal biopsies in PROTECT UC [206 UC and 20 controls (Ctl)]. Weighted gene co-expression network analysis (WGCNA) to identify modules and gens associated with UC severity, week 4 remission after 5-ASA/steroids (W4R), week 52 steroid-free remission (W52SFR), and colectomy within 3 years. Epithelial mechanistic data of prioritized lncRNA. Results PROTECT transriptomics included 2,826 lncRNA genes with TPM>1 in 20% of samples. Principal components analysis (PCA, Fig 1) using these lncRNA showed distinct clusters of UC and Ctl, and PC2 values were linked (p<0.01) with endoscopic (Mayo score) and clinical (PUCAI) disease severities. Random forest classifiers using the 2,826 lncRNA trained to distinguish UC from Ctl using PROTECT, predicted the correct diagnosis in PROTECT (AUC=1) and in RISK (AUC=0.88) connecting lncRNA to UC pathogenesis in two independent cohorts. WGCNA on the 2,826 lncRNA resulted in 6 modules (M1-M6) associated with UC (p<0.01, Fig 2). M1, which contained lncRNA reduced in UC, was associated with lessW4R (p=0.01) less W52SFR (p=0.04) and increased colectomy (p=0.02). In contrast, M6, which contained lncRNA elevated in UC, was linked with W4R (p=0.008). The hub genes in the M1 and M6 modules included GATA6-AS1 and LINC01272 lncRNAs, respectively. Re-analysis of single cell datasets supported epithelial expression of GATA6-AS1 and myeloid expression of LINC01272. GATA6-AS1 co-expression with protein-coding genes in PROTECT showed significant enrichment for mitochondrial functions (p<1E-40). Reduction of GATA6-AS1 expression with 2 shRNAs resulted in reduced mitochondrial complex IV MT-CO2 mRNA and protein and reduction of LGR5, linking mitochondrial genes and function with epithelial renewal. We recently showed pronounced reduction of the mitochondrial membrane potential (MMP) by JC-1 staining in UC epithelia. Consistent with this finding, GATA6-AS1 inhibition reduced MMP levels from 0.22 in control to 0.08 (p=0.01), similarly to MMP of cells treated with CCCP that is known to depolarize and reduce MMP. Conclusion LncRNA are significantly linked with UC and disease severity, and the M1 epithelial enriched module shows significant association with worse outcome. GATA6-AS1 within the M1 hub genes show potential role in epithelial metabolic functions and renewal.
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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 | 0.000 |
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".