set-2
C. elegans
Histone-lysine N-methyltransferase set-2
What the model saw
Gene: set-2 Organism: Caenorhabditis elegans Known functions: Histone-lysine N-methyltransferase set-2. RNA binding. histone H3K4 methyltransferase activity. histone H3K4 trimethyltransferase activity. nucleic acid binding.
View unredacted entry
Histone-lysine N-methyltransferase set-2. RNA binding. histone H3K4 methyltransferase activity. histone H3K4 trimethyltransferase activity. nucleic acid binding.
Solver output
SET-2 is the C. elegans ortholog of the COMPASS complex methyltransferase responsible for histone H3 lysine 4 mono-, di-, and trimethylation (H3K4me1/2/3), marks associated with active transcription and chromatin accessibility. H3K4me3 at gene promoters is a key epigenetic mark that maintains proper gene expression programs; its progressive loss with age is a hallmark of epigenetic deterioration. In C. elegans, H3K4me3 levels and the COMPASS complex have been directly linked to lifespan regulation: loss of H3K4 methyltransferase activity (e.g., via ash-2 or wdr-5 subunit mutations) can extend lifespan, suggesting that SET-2 activity itself promotes a transcriptional state that is permissive for normal development but may limit maximal longevity. However, SET-2 also maintains transcriptional fidelity and stress-response gene expression, and its loss causes accelerated epigenetic aging phenotypes. The balance of evidence in C. elegans places SET-2 as a pro-longevity factor when its activity is considered in the context of maintaining proper chromatin states and stress-response gene regulation, though some studies show complex, context-dependent effects.
GenAge curators classify each gene's normal function as promoting (Pro-Longevity) or opposing (Anti-Longevity) longevity, based on synthesis across studies. Loss-of-function effects can vary from this depending on the manipulation.
Advisor judgment
The model predicted pro_longevity but the ground truth is anti_longevity. The model's reasoning is internally contradictory - it correctly notes that loss of H3K4 methyltransferase activity (via ash-2 or wdr-5 mutations) extends lifespan, which would make SET-2 anti-longevity (since SET-2 is the catalytic subunit of the same COMPASS complex). However, the model then incorrectly concludes SET-2 is pro_longevity, contradicting its own mechanistic reasoning. The literature clearly shows that set-2 loss-of-function extends lifespan in C. elegans, making it anti_longevity. The model had the right mechanistic information but drew the wrong conclusion, and showed moderate-high confidence (0.72) in the wrong answer.
Raw API responses
solver
{
"reasoning": "SET-2 is the C. elegans ortholog of the COMPASS complex methyltransferase responsible for histone H3 lysine 4 mono-, di-, and trimethylation (H3K4me1/2/3), marks associated with active transcription and chromatin accessibility. H3K4me3 at gene promoters is a key epigenetic mark that maintains proper gene expression programs; its progressive loss with age is a hallmark of epigenetic deterioration. In C. elegans, H3K4me3 levels and the COMPASS complex have been directly linked to lifespan regulation: loss of H3K4 methyltransferase activity (e.g., via ash-2 or wdr-5 subunit mutations) can extend lifespan, suggesting that SET-2 activity itself promotes a transcriptional state that is permissive for normal development but may limit maximal longevity. However, SET-2 also maintains transcriptional fidelity and stress-response gene expression, and its loss causes accelerated epigenetic aging phenotypes. The balance of evidence in C. elegans places SET-2 as a pro-longevity factor when its activity is considered in the context of maintaining proper chromatin states and stress-response gene regulation, though some studies show complex, context-dependent effects.",
"confidence": 0.72,
"key_pathways": [
"H3K4 trimethylation / COMPASS complex",
"Epigenetic regulation of gene expression",
"Chromatin-based transcriptional memory and stress response"
],
"mechanism_class": "epigenetic_alterations",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity but the ground truth is anti_longevity. The model's reasoning is internally contradictory - it correctly notes that loss of H3K4 methyltransferase activity (via ash-2 or wdr-5 mutations) extends lifespan, which would make SET-2 anti-longevity (since SET-2 is the catalytic subunit of the same COMPASS complex). However, the model then incorrectly concludes SET-2 is pro_longevity, contradicting its own mechanistic reasoning. The literature clearly shows that set-2 loss-of-function extends lifespan in C. elegans, making it anti_longevity. The model had the right mechanistic information but drew the wrong conclusion, and showed moderate-high confidence (0.72) in the wrong answer.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}