let-418
C. elegans
Protein let-418
What the model saw
Gene: let-418 Organism: Caenorhabditis elegans Known functions: Protein let-418. ATP binding. ATP hydrolysis activity. ATP-dependent chromatin remodeler activity. DNA binding. RNA polymerase II transcription regulatory region sequence-specific DNA binding. RNA polymerase II-specific DNA-binding transcription factor binding. chromatin binding. histone binding. protein binding.
View unredacted entry
Protein let-418. ATP binding. ATP hydrolysis activity. ATP-dependent chromatin remodeler activity. DNA binding. RNA polymerase II transcription regulatory region sequence-specific DNA binding. RNA polymerase II-specific DNA-binding transcription factor binding. chromatin binding. histone binding. protein binding.
Solver output
let-418 is the C. elegans ortholog of Mi-2/CHD3/CHD4, the catalytic ATPase subunit of the NuRD (Nucleosome Remodeling and Deacetylase) chromatin remodeling complex. Its ATP-dependent chromatin remodeler activity, histone binding, and RNA Pol II transcription factor binding place it as a master regulator of chromatin accessibility and transcriptional repression. In C. elegans, let-418/NuRD functions within the synthetic multivulva (synMuv B) pathway and cooperates with the DRM complex to repress germline and stress-response genes in somatic tissues. Maintenance of proper chromatin compaction and transcriptional fidelity via NuRD activity helps preserve epigenetic homeostasis, which is a key determinant of longevity. Loss of let-418 function leads to derepression of germline gene programs in somatic cells, a hallmark of epigenetic dysregulation associated with shortened lifespan, suggesting the wild-type gene's repressive chromatin remodeling activity is protective and pro-longevity.
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 correctly identified let-418 as the Mi-2/NuRD complex ATPase subunit and its role in chromatin remodeling and synMuv B pathway. However, the mechanistic reasoning led to the wrong conclusion. The model argued that loss of let-418 causes derepression of germline genes and epigenetic dysregulation, which would shorten lifespan — implying the wild-type is pro-longevity. In reality, let-418 is anti_longevity, meaning its activity reduces lifespan (or its loss extends lifespan). The actual literature shows that RNAi knockdown of let-418 extends lifespan in C. elegans, likely because NuRD-mediated repression of stress response or longevity genes is relieved. The model's reasoning about germline derepression shortening lifespan was plausible but incorrect in this context — the NuRD complex represses longevity-promoting programs, so its loss extends lifespan. The model had moderate confidence (0.62) but still got the direction wrong.
Raw API responses
solver
{
"reasoning": "let-418 is the C. elegans ortholog of Mi-2/CHD3/CHD4, the catalytic ATPase subunit of the NuRD (Nucleosome Remodeling and Deacetylase) chromatin remodeling complex. Its ATP-dependent chromatin remodeler activity, histone binding, and RNA Pol II transcription factor binding place it as a master regulator of chromatin accessibility and transcriptional repression. In C. elegans, let-418/NuRD functions within the synthetic multivulva (synMuv B) pathway and cooperates with the DRM complex to repress germline and stress-response genes in somatic tissues. Maintenance of proper chromatin compaction and transcriptional fidelity via NuRD activity helps preserve epigenetic homeostasis, which is a key determinant of longevity. Loss of let-418 function leads to derepression of germline gene programs in somatic cells, a hallmark of epigenetic dysregulation associated with shortened lifespan, suggesting the wild-type gene's repressive chromatin remodeling activity is protective and pro-longevity.",
"confidence": 0.62,
"key_pathways": [
"NuRD chromatin remodeling complex / ATP-dependent nucleosome repositioning",
"synMuv B transcriptional repression pathway",
"RNA Pol II transcription regulation and epigenetic silencing"
],
"mechanism_class": "epigenetic_alterations",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity but the ground truth is anti_longevity. The model correctly identified let-418 as the Mi-2/NuRD complex ATPase subunit and its role in chromatin remodeling and synMuv B pathway. However, the mechanistic reasoning led to the wrong conclusion. The model argued that loss of let-418 causes derepression of germline genes and epigenetic dysregulation, which would shorten lifespan — implying the wild-type is pro-longevity. In reality, let-418 is anti_longevity, meaning its activity reduces lifespan (or its loss extends lifespan). The actual literature shows that RNAi knockdown of let-418 extends lifespan in C. elegans, likely because NuRD-mediated repression of stress response or longevity genes is relieved. The model's reasoning about germline derepression shortening lifespan was plausible but incorrect in this context — the NuRD complex represses longevity-promoting programs, so its loss extends lifespan. The model had moderate confidence (0.62) but still got the direction wrong.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}