Promoter methylation in a mixed feedback loop circadian clock model
Bibliographic record
Abstract
We investigate how epigenetic modifications to clock gene promoters affect transcriptomic activity in the circadian clock. Motivated by experimental observations that link DNA methylation with the behavior of the clock, we introduce and analyze an extension of the mixed feedback loop (MFL) model of François and Hakim. We extend the original model to include an additional methylated promoter state and allow for reversible protein sequestration, an important feature for circadian applications. First, working with the general form of the MFL model, we find that the qualitative behavior of the model is dictated by the promoter state with the highest transcription rate. We then build on the work of Kim and Forger, who analyzed the stability of the mammalian circadian clock by using a reduced form of the MFL model. We present a rigorous procedure for translating between the MFL model and the reduction of Kim and Forger. We then propose a model reduction more appropriate for the study of oscillatory promoter states, making use of a fully coupled quasi-steady-state approximation rather than the standard partially uncoupled quasi-steady-state approach. Working with the novel reduced form of the model, we find substantial differences in the transcription function and show that, although methylation contributes to period control, excessive methylation can abolish rhythmicity. Altogether our results show that even in a minimal clock model, DNA methylation has a nontrivial influence on the system's ability to oscillate.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| 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".