SET2
S. cerevisiae
histone methyltransferase SET2
What the model saw
Gene: SET2 Organism: Saccharomyces cerevisiae Known functions: histone methyltransferase SET2. RNA binding. histone H3K36 methyltransferase activity. histone H3K36 trimethyltransferase activity. histone methyltransferase activity. methyltransferase activity. protein binding. zinc ion binding.
View unredacted entry
histone methyltransferase SET2. RNA binding. histone H3K36 methyltransferase activity. histone H3K36 trimethyltransferase activity. histone methyltransferase activity. methyltransferase activity. protein binding. zinc ion binding.
Solver output
SET2 is the sole histone H3K36 methyltransferase in S. cerevisiae, responsible for mono-, di-, and trimethylation of H3K36, a mark deposited co-transcriptionally by the elongating RNA Pol II complex. H3K36me3 recruits the Rpd3S histone deacetylase complex to suppress cryptic intragenic transcription, but the mark itself also contributes to age-associated transcriptional noise and altered chromatin states. Loss of H3K36 methylation (set2Δ) has been reported to extend replicative lifespan in yeast, suggesting that SET2 activity normally limits longevity. This fits the broader paradigm in which progressive epigenetic drift—including changes in histone methylation patterns—is a hallmark of aging; SET2-mediated H3K36 methylation appears to promote this drift rather than counteract it. Additionally, H3K36me antagonizes H3K27me3 spreading and interacts with Sir protein-mediated silencing at subtelomeric regions, further linking SET2 to age-related chromatin reorganization.
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 correctly predicted SET2 as anti_longevity with a reasonable confidence of 0.72. The mechanistic reasoning is solid: SET2 is indeed the H3K36 methyltransferase in yeast, and loss of SET2 (set2Δ) has been shown to extend replicative lifespan, making SET2 anti-longevity. The model correctly identifies the H3K36me3/Rpd3S axis and the role of epigenetic drift in aging. The reasoning about cryptic transcription suppression and age-related chromatin reorganization is accurate. The model slightly overcomplicates the explanation with the H3K27me3 antagonism point (less directly relevant in yeast), but overall the mechanistic reasoning is correct and well-grounded.
Raw API responses
solver
{
"reasoning": "SET2 is the sole histone H3K36 methyltransferase in S. cerevisiae, responsible for mono-, di-, and trimethylation of H3K36, a mark deposited co-transcriptionally by the elongating RNA Pol II complex. H3K36me3 recruits the Rpd3S histone deacetylase complex to suppress cryptic intragenic transcription, but the mark itself also contributes to age-associated transcriptional noise and altered chromatin states. Loss of H3K36 methylation (set2Δ) has been reported to extend replicative lifespan in yeast, suggesting that SET2 activity normally limits longevity. This fits the broader paradigm in which progressive epigenetic drift—including changes in histone methylation patterns—is a hallmark of aging; SET2-mediated H3K36 methylation appears to promote this drift rather than counteract it. Additionally, H3K36me antagonizes H3K27me3 spreading and interacts with Sir protein-mediated silencing at subtelomeric regions, further linking SET2 to age-related chromatin reorganization.",
"confidence": 0.72,
"key_pathways": [
"H3K36 methylation / Rpd3S deacetylase axis",
"co-transcriptional chromatin modification",
"epigenetic regulation of replicative lifespan"
],
"mechanism_class": "epigenetic_alterations",
"longevity_influence": "anti_longevity"
}advisor
{
"notes": "The model correctly predicted SET2 as anti_longevity with a reasonable confidence of 0.72. The mechanistic reasoning is solid: SET2 is indeed the H3K36 methyltransferase in yeast, and loss of SET2 (set2Δ) has been shown to extend replicative lifespan, making SET2 anti-longevity. The model correctly identifies the H3K36me3/Rpd3S axis and the role of epigenetic drift in aging. The reasoning about cryptic transcription suppression and age-related chromatin reorganization is accurate. The model slightly overcomplicates the explanation with the H3K27me3 antagonism point (less directly relevant in yeast), but overall the mechanistic reasoning is correct and well-grounded.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 4,
"ground_truth_questionable": false
}