Characterization of the cardiac KCNE1 gene promoter
Bibliographic record
Abstract
BACKGROUND: KCNE1 encodes an essential cardiac slow delayed-rectifier potassium current (I(Ks)) beta-subunit (minK). Varying minK expression is important in disease-related remodeling and species-dependent expression. This study addressed 5'-regulatory elements that potentially control KCNE1 transcription. METHODS AND RESULTS: The transcriptional start site of human KCNE1 (HKCNE1) was determined with 5'RACE. Of four isoforms, the putative promoter driving the isoforms constituting >80% expression in human hearts was further analyzed. A 1625-bp region 5' to the transcriptional start site was subcloned into luciferase-reporter plasmid (PGL3-Basic). The full promoter sequence increased luciferase expression 31-fold in neonatal rat cardiomyocytes (NRMs). A much smaller 327-bp core promoter maintained activity 21-29 fold. The core promoter conferred cardiomyocyte-preferential expression, with an activity in NRMs 4.9-fold greater than in Chinese Hamster Ovary cells (CHOs), compared to approximately 2.0 for the full-length promoter. Site-directed mutagenesis of all three GATA elements in the core promoter reduced its activity by >50% and attenuated cardiomyocyte-preferential expression. Mutagenesis of the second GATA element alone decreased promoter activity by approximately 50%. GATA4 knockdown with siRNA inhibited approximately 40% of core promoter activity in NRMs. Angiotensin-II increased HKCNE1 promoter activity, but only in the presence of intact GATA elements. The typically low-level I(Ks) expression in mouse and rabbit is related to low minK expression. Cloning of the mouse KCNE1 (MKCNE1) 5'-regulatory region showed approximately 50% sequence identity to human. MKCNE1 had only 1 GATA element in the region corresponding to the human core promoter and had less promoter activity (11.7 vs 29.0-fold PGL3-Basic for human). CONCLUSION: Promoter elements in the HKCNE1 5'-end, particularly GATA binding sites, may be important in tissue, disease and species-related transcriptional regulation of I(Ks).
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| 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".