Divergent regulation of the<i>Osteopontin</i>promoter by the estrogen receptor-related receptors is isoform- and cell context dependent
Bibliographic record
Abstract
We sought to determine whether the estrogen receptor-related receptor gamma (mEsrrg) regulated the Osteopontin (Opn) promoter through the same AP1/CAAT box element that we have previously described for mEsrra. In HeLa cells mEsrrg used an additional site present in the 5'UTR, while in ROS17/2.8 cells the AP1/CAAT site was not used, but a completely novel site surrounding the transcription start site was used. We also find that in ROS17/2.8 cells mEsrra repressed, while mEsrrg activated the Opn promoter. None of the sites identified conform to established Esrr response elements (ERREs). Additionally, the two reported mEsrrg protein isoforms showed differences in their activation potential. Mutations in the activation function 2 (AF2) of mEsrra, predicted to abolish activation, surprisingly turned mEsrra into a better activator. In contrast, similar AF2 mutations in Esrrg2 abolished its ability to activate the Opn promoter. Mutation of the DNA binding domain of mEsrra/g2 abolished transcriptional activity in HeLa and ROS17/2.8 cells. Our data indicate, first, that the two Esrr isoforms regulate Opn in a cell context-dependent manner. Second, they suggest that although the DNA binding domains of mEsrra and mEsrrg are 93% identical and required for regulation, the receptors bind to distinct Opn promoter elements, suggesting that the two isoforms may co-regulate Opn, and perhaps other genes, without competing for the same site in the promoter. Finally, the results suggest that each isoform interacts differently with co-activators and co-repressors, as highlighted by the AF2 mutation that turns mEsrra into a better activator but abolishes activity of Esrrg2.
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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 | 0.000 | 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) | 0.000 | 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".