Regulation of scleraxis‐mediated cardiac fibrotic gene expression by serine phosphorylation
Bibliographic record
Abstract
Cardiac fibrosis is a major clinical problem that affects millions of people worldwide yet lacks any specific therapy. Our laboratory was the first to demonstrate the bHLH transcription factor scleraxis induces collagen Iα2 expression in cardiac fibroblasts and myofibroblasts. Scleraxis was also found to be up‐regulated in the heart post‐myocardial infarction, suggesting its role in cardiac pathogenesis. Here we identify a novel mechanism by which scleraxis activity is regulated and determine its effect on genes targeted by scleraxis. Putative phosphorylation sites on scleraxis were revealed by in silico analysis using motif prediction software. Mutation of this phosphorylatable motif to a non‐phosphorylatable form significantly attenuated the expression of fibrillar type I collagen and myofibroblast marker genes normally induced by scleraxis. Down‐regulation of collagen Iα2 expression was due to reduced binding of the non‐phosphorylated scleraxis mutant to specific DNA‐binding sites (E‐boxes) within the promoter as determined by chromatin immunoprecipitation in human cardiac fibroblast cells and electrophoretic mobility shift assay. This is the first evidence suggesting that scleraxis is likely phosphorylated under basal conditions. Analysis of the phosphorylation motif suggested the possible regulation of scleraxis activity by casein kinase 2 (CK2). Inhibition of CK2 activity disrupted the ability of scleraxis to modulate the expression of its target genes. This presents a novel mechanism for regulation of scleraxis activity and thereby provides a rationale for targeting scleraxis for development of drugs to treat cardiac fibrosis.
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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) | 0.000 | 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) | 0.000 | 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".