Referee report. For: Transcription factor binding site clusters identify target genes with similar tissue-wide expression and buffer against mutations [version 2; peer review: 2 approved]
Bibliographic record
Abstract
Background: The distribution and composition of cis -regulatory modules composed of transcription factor (TF) binding site (TFBS) clusters in promoters substantially determine gene expression patterns and TF targets. TF knockdown experiments have revealed that TF binding profiles and gene expression levels are correlated. We use TFBS features within accessible promoter intervals to predict genes with similar tissue-wide expression patterns and TF targets using Machine Learning (ML). Methods: Bray-Curtis Similarity was used to identify genes with correlated expression patterns across 53 tissues. TF targets from knockdown experiments were also analyzed by this approach to set up the ML framework. TFBSs were selected within DNase I-accessible intervals of corresponding promoter sequences using information theory-based position weight matrices (iPWMs) for each TF. Features from information-dense clusters of TFBSs were input to ML classifiers which predict these gene targets along with their accuracy, specificity and sensitivity. Mutations in TFBSs were analyzed in silico to examine their impact on TFBS clustering and predict changes in gene regulation. Results: The glucocorticoid receptor gene ( NR3C1 ), whose regulation has been extensively studied, was selected to test this approach. SLC25A32 and TANK exhibited the most similar expression patterns to NR3C1 . A Decision Tree classifier exhibited the best performance in detecting such genes, based on Area Under the Receiver Operating Characteristic curve (ROC). TF target gene prediction was confirmed using siRNA knockdown, which was more accurate than CRISPR/CAS9 inactivation. TFBS mutation analyses revealed that accurate target gene prediction required at least 1 information-dense TFBS cluster. Conclusions : ML based on TFBS information density, organization, and chromatin accessibility accurately identifies gene targets with comparable tissue-wide expression patterns. Multiple information-dense TFBS clusters in promoters appear to protect promoters from effects of deleterious binding site mutations in a single TFBS that would otherwise alter regulation of these genes.
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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 | 0.005 | 0.064 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.004 | 0.004 |
| Science and technology studies | 0.003 | 0.001 |
| Scholarly communication | 0.003 | 0.003 |
| Open science | 0.003 | 0.003 |
| Research integrity | 0.004 | 0.003 |
| Insufficient payload (model declined to judge) | 0.712 | 0.440 |
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".