hdac1
D. melanogaster
Histone deacetylase 1
What the model saw
Gene: HDAC1 Organism: Drosophila melanogaster Known functions: Histone deacetylase 1. histone deacetylase 1. DNA-binding transcription factor binding. histone H4K12 deacetylase activity, hydrolytic mechanism. histone H4K16 deacetylase activity, hydrolytic mechanism. histone H4K5 deacetylase activity, hydrolytic mechanism. histone H4K8 deacetylase activity, hydrolytic mechanism. histone deacetylase activity. histone deacetylase activity, hydrolytic mechanism. protein binding. transcription corepressor activity.
View unredacted entry
Histone deacetylase 1. histone deacetylase 1. DNA-binding transcription factor binding. histone H4K12 deacetylase activity, hydrolytic mechanism. histone H4K16 deacetylase activity, hydrolytic mechanism. histone H4K5 deacetylase activity, hydrolytic mechanism. histone H4K8 deacetylase activity, hydrolytic mechanism. histone deacetylase activity. histone deacetylase activity, hydrolytic mechanism. protein binding. transcription corepressor activity.
Solver output
HDAC1 is a class I histone deacetylase that removes acetyl groups from histone H4 at lysines K5, K8, K12, and K16, promoting chromatin compaction and transcriptional repression. Maintenance of proper histone deacetylation patterns is critical for preserving the epigenome during aging; loss of HDAC activity leads to global histone hyperacetylation, chromatin decompaction, and aberrant gene expression—hallmarks of epigenetic drift associated with aging. In particular, deacetylation of H4K16 (a mark strongly linked to chromatin opening and aging-associated transcriptional noise) by HDAC1 helps maintain heterochromatin integrity and silences repetitive elements and pro-aging gene programs. HDAC1 also acts as a transcription corepressor, suppressing expression of genes that can drive cellular senescence or stress responses when inappropriately activated. Evidence from model organisms including Drosophila supports that HDAC activity (Rpd3, the fly ortholog of HDAC1) modulates lifespan, with reduced Rpd3 activity extending lifespan in some contexts, suggesting the normal function of HDAC1 in maintaining epigenetic homeostasis is broadly pro-longevity, though context-dependent effects complicate the picture.
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." Notably, the model's own reasoning actually contains the key evidence that contradicts its conclusion: it mentions that "reduced Rpd3 activity extending lifespan in some contexts" — which directly implies that HDAC1/Rpd3 is anti-longevity (its reduction extends life). Despite acknowledging this critical fact, the model still concluded pro_longevity, which is internally inconsistent. The mechanistic reasoning is also flawed: the model argues HDAC1 maintains epigenetic homeostasis and is therefore pro-longevity, but the actual finding in Drosophila is that reducing Rpd3/HDAC1 extends lifespan, making it anti-longevity. The model contradicted itself and reached the wrong conclusion with moderate confidence (0.65).
Raw API responses
solver
{
"reasoning": "HDAC1 is a class I histone deacetylase that removes acetyl groups from histone H4 at lysines K5, K8, K12, and K16, promoting chromatin compaction and transcriptional repression. Maintenance of proper histone deacetylation patterns is critical for preserving the epigenome during aging; loss of HDAC activity leads to global histone hyperacetylation, chromatin decompaction, and aberrant gene expression—hallmarks of epigenetic drift associated with aging. In particular, deacetylation of H4K16 (a mark strongly linked to chromatin opening and aging-associated transcriptional noise) by HDAC1 helps maintain heterochromatin integrity and silences repetitive elements and pro-aging gene programs. HDAC1 also acts as a transcription corepressor, suppressing expression of genes that can drive cellular senescence or stress responses when inappropriately activated. Evidence from model organisms including Drosophila supports that HDAC activity (Rpd3, the fly ortholog of HDAC1) modulates lifespan, with reduced Rpd3 activity extending lifespan in some contexts, suggesting the normal function of HDAC1 in maintaining epigenetic homeostasis is broadly pro-longevity, though context-dependent effects complicate the picture.",
"confidence": 0.65,
"key_pathways": [
"Histone H4 deacetylation and chromatin compaction",
"Transcriptional repression via corepressor complexes (e.g., Sin3/NuRD)",
"Heterochromatin maintenance and silencing of repetitive elements"
],
"mechanism_class": "epigenetic_alterations",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted \"pro_longevity\" but the ground truth is \"anti_longevity.\" Notably, the model's own reasoning actually contains the key evidence that contradicts its conclusion: it mentions that \"reduced Rpd3 activity extending lifespan in some contexts\" — which directly implies that HDAC1/Rpd3 is anti-longevity (its reduction extends life). Despite acknowledging this critical fact, the model still concluded pro_longevity, which is internally inconsistent. The mechanistic reasoning is also flawed: the model argues HDAC1 maintains epigenetic homeostasis and is therefore pro-longevity, but the actual finding in Drosophila is that reducing Rpd3/HDAC1 extends lifespan, making it anti-longevity. The model contradicted itself and reached the wrong conclusion with moderate confidence (0.65).",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}