HIR3
S. cerevisiae
Hir3p
What the model saw
Gene: HIR3 Organism: Saccharomyces cerevisiae Known functions: Hir3p. DNA binding. nucleosome binding. protein binding. transcription corepressor activity.
View unredacted entry
Hir3p. DNA binding. nucleosome binding. protein binding. transcription corepressor activity.
Solver output
HIR3 encodes a subunit of the HIR (Histone Regulatory) complex in S. cerevisiae, which functions as a histone chaperone and transcription corepressor that binds nucleosomes and DNA to repress histone gene expression outside of S phase. By maintaining proper histone stoichiometry and nucleosome occupancy, the HIR complex helps preserve chromatin integrity and epigenetic silencing — particularly at subtelomeric regions and repetitive loci. Loss of chromatin-based transcriptional repression is a hallmark of aging in yeast, where erosion of silencing at rDNA and telomeres contributes to genomic instability and shortened lifespan. The nucleosome-binding and corepressor activities of Hir3p support stable heterochromatin and suppress aberrant transcription, which is protective against age-associated epigenetic drift. Therefore, the normal function of HIR3 is expected to be pro-longevity by maintaining epigenetic integrity.
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 HIR3 as pro_longevity, but the ground truth is anti_longevity. The model's reasoning was plausible on the surface — it correctly identified HIR3 as part of the HIR histone chaperone complex with corepressor activity — but drew the wrong conclusion about its effect on lifespan. In yeast, deletion of HIR3 (and other HIR complex members) has been shown to extend lifespan, meaning HIR3 normally acts to limit longevity (anti_longevity). The model's mechanistic reasoning about chromatin silencing being protective was logically coherent but ultimately incorrect in its application to HIR3 specifically. The model was moderately confident (0.62) in the wrong direction.
Raw API responses
solver
{
"reasoning": "HIR3 encodes a subunit of the HIR (Histone Regulatory) complex in S. cerevisiae, which functions as a histone chaperone and transcription corepressor that binds nucleosomes and DNA to repress histone gene expression outside of S phase. By maintaining proper histone stoichiometry and nucleosome occupancy, the HIR complex helps preserve chromatin integrity and epigenetic silencing — particularly at subtelomeric regions and repetitive loci. Loss of chromatin-based transcriptional repression is a hallmark of aging in yeast, where erosion of silencing at rDNA and telomeres contributes to genomic instability and shortened lifespan. The nucleosome-binding and corepressor activities of Hir3p support stable heterochromatin and suppress aberrant transcription, which is protective against age-associated epigenetic drift. Therefore, the normal function of HIR3 is expected to be pro-longevity by maintaining epigenetic integrity.",
"confidence": 0.62,
"key_pathways": [
"HIR histone chaperone complex / histone gene repression",
"chromatin silencing and nucleosome assembly",
"epigenetic maintenance of heterochromatin"
],
"mechanism_class": "epigenetic_alterations",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted HIR3 as pro_longevity, but the ground truth is anti_longevity. The model's reasoning was plausible on the surface — it correctly identified HIR3 as part of the HIR histone chaperone complex with corepressor activity — but drew the wrong conclusion about its effect on lifespan. In yeast, deletion of HIR3 (and other HIR complex members) has been shown to extend lifespan, meaning HIR3 normally acts to limit longevity (anti_longevity). The model's mechanistic reasoning about chromatin silencing being protective was logically coherent but ultimately incorrect in its application to HIR3 specifically. The model was moderately confident (0.62) in the wrong direction.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}