Scleraxis Regulation of Snail1 and Twist1 Gene Expression in Epithelial – Mesenchymal Transition
Bibliographic record
Abstract
Epithelial‐Mesenchymal Transition (EMT) is a process by which epithelial cells lose their connectivity with each other and convert to a migratory, mesenchymal phenotype, and plays an important role in development as well as pathogenesis of diseases such as cancer and fibrosis. EMT is induced in part by the up‐regulation of the transcription factors Twist1 as well as Snai1, which directly represses transcription of E‐cadherin, an integral component of adherens junctions: tight cell‐cell connections prominent in epithelial cell sheets. Our previous data in mice demonstrated that gene knockout of the transcription factor scleraxis, which is involved in cell phenotype conversion, resulted in fewer cardiac fibroblasts, which arise developmentally from proepicardial cells undergoing EMT. We observed an increase in epithelial markers concomitant with a loss of mesenchymal markers in scleraxis null hearts, suggesting that EMT was impaired by scleraxis deletion. Our data indicated that scleraxis directly transactivates the Twist1 and Snail1 gene promoters, and that scleraxis was sufficient to induce EMT in A549 epithelial cells, but the mechanistic details of this regulation were unclear. Here we examined the Twist1 and Snail1 gene promoters for E‐boxes – CANNTG sequences to which scleraxis binds. By in silico analysis, we identified one and four putative E‐boxes in the Twist1 and Snail1 proximal promoters, respectively. Using luciferase reporter assays, we found that scleraxis directly transactivated both promoters. The single E‐box in the Twist1 promoter was required for this effect, as mutation of the E‐box abolished scleraxis‐mediated reporter induction. Conversely, three out of four E‐boxes within the Snail1 promoter were similarly required. Results for both studies were confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays, which demonstrated that scleraxis directly interacted with the E‐boxes in question. Scleraxis over‐expression resulted in up‐regulation of both Snail1 and Twist1, and increased migration of A549 epithelial cells as measured via scratch assay, indicating progression of EMT. TGFβ 1 , a known inducer of both EMT and scleraxis expression, increased Snail1 and Twist1 expression, but scleraxis knockdown via shRNA attenuated this induction, demonstrating that TGFβ 1 ‐mediated EMT requires scleraxis. These findings suggest that scleraxis is an important factor in driving EMT, and may be a novel therapeutic target to arrest cell conversion in EMT‐dependent pathological processes. Support or Funding Information DSA was supported by funding from the GETS program of the University of Manitoba. MPC was supported by an Open Operating Grant from the Canadian Institutes of Health Research (MOP136862). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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".