A nuclear-targeted activity-based sensing probe for ratiometric imaging of formaldehyde reveals endogenous epigenetic contributors to the nuclear formaldehyde pool
Bibliographic record
Abstract
Formaldehyde (FA) is both a one-carbon (1C) metabolite and a potent genotoxin in living cells. FA plays beneficial roles in endogenous catabolic processes and cellular signaling, but its potent electrophilicity necessitates strict regulation. This dichotomy is especially important in the nucleus, where endogenously produced FA has been shown to promote toxicity and disease by generating deleterious DNA adducts. More broadly, the sources and scavenging mechanisms of FA differ across subcellular compartments, underscoring the need for imaging sensors with subcellular spatial resolution to accurately probe contributions of FA to transient, local 1C pools. Here, we report NucRFAP-2, a nuclear-targeted, activity-based ratiometric probe for FA detection, and apply it to monitor dynamic changes in the nuclear FA pool. Using this first-generation reagent for nuclear FA imaging, we demonstrate that genetic perturbation of key FA clearance pathways alters nuclear FA levels by identifying alcohol dehydrogenase 5 (ADH5) as a principal regulator of nuclear FA homeostasis. Furthermore, NucRFAP-2 reveals elevated nuclear FA pools in patient-derived T and B lymphocytes deficient in Wiskott-Aldrich syndrome protein (WASp) and Fanconi anemia group D2 protein (FANCD2), suggesting that replication-associated epigenetic rewiring may contribute to aldehyde-associated pathologies. By demonstrating the ability of NucRFAP-2 to reveal an interplay between FA metabolism, genome integrity, and 1C homeostasis, we showcase this probe as a potentially powerful chemical tool to uncover novel mechanisms of nuclear FA biology.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.003 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 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".