Inflammatory bowel disease risk gene C1ORF106 regulates actin dynamics in intestinal epithelial cells
Bibliographic record
Abstract
Background and aims: C1ORF106 has previously been associated with inflammatory bowel diseases (IBD) via large-scale genetic studies. Increased intestinal permeability is a hallmark of IBD and is observed in at-risk individuals prior to the appearance of clinical symptoms. C1ORF106 was previously shown to regulate intestinal barrier permeability through the regulation of adherens junction stability and through the formation of tight junctions, which impacted actin assembly. However, the downstream impact and molecular mechanisms involved in actin regulation by C1ORF106 haven't been explored. Our study aimed at identifying which pathways involved in intestinal epithelial barrier regulation and F-actin regulation are impacted by C1ORF106 and its IBD-associated variant. Methods: in human colonic epithelial cells and characterized the function of the 333F variant in intestinal epithelial spheroid cultures obtained from patient-derived human induced pluripotent stem cell (hiPSC). We measured barrier permeability and characterized spheroid formation, actin regulation and cell migration though immunofluorescence, western blots and permeability assays. Results: C1ORF106 KD leads to impaired cortical actin belt dynamics and regulation of stress fiber formation, resulting in increased cell constriction, impaired barrier permeability, cell polarity and cell migration. Moreover, we demonstrated that an inhibition of ROCK rescues the actin belt and cell polarity phenotypes in C1ORF106 KD cells, demonstrating that C1ORF106 regulates these phenotypes through a ROCK-dependent mechanism. We also observed an altered nmMYO2-P localization in C1ORF106 KD cells associated with the formation of Vacuolar Apical Compartments (VACs), which are important for 3D epithelial spheroid formation. We observed a similar impact on cell polarity in intestinal epithelial spheroids obtained from hiPSC carrying the 333F variant, providing additional support that this pathway is involved in disease development. Conclusion: We provide insights into the molecular mechanisms by which C1ORF106 controls actin dynamics to regulate intestinal epithelial integrity.
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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) | 0.001 | 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".