NAT4
S. cerevisiae
N-terminal L-serine N(alpha)-acetyltransferase NatD
What the model saw
Gene: NAT4 Organism: Saccharomyces cerevisiae Known functions: N-terminal L-serine N(alpha)-acetyltransferase NatD. acyltransferase activity, transferring groups other than amino-acyl groups. histone H2A acetyltransferase activity. histone H4 acetyltransferase activity. protein N-terminal-serine acetyltransferase activity.
View unredacted entry
N-terminal L-serine N(alpha)-acetyltransferase NatD. acyltransferase activity, transferring groups other than amino-acyl groups. histone H2A acetyltransferase activity. histone H4 acetyltransferase activity. protein N-terminal-serine acetyltransferase activity.
Solver output
NAT4 (NatD) is the N-terminal acetyltransferase responsible for co-translational Nα-acetylation of histones H4 and H2A at their N-terminal serine residues. This modification is a conserved epigenetic mark on the histone tail that influences chromatin compaction and gene silencing. Proper N-terminal acetylation of histone H4 is linked to maintenance of heterochromatin structure and transcriptional regulation, processes critical for genomic stability and silencing of repetitive elements during aging. Loss of histone H4 Nα-acetylation disrupts chromatin integrity and has been associated with reduced replicative lifespan in yeast, as chromatin-based silencing (e.g., at rDNA and telomeres) is a key determinant of yeast longevity. Thus, NAT4's normal function in maintaining the histone H4/H2A epigenetic acetylation mark supports chromatin homeostasis and opposes age-associated epigenetic drift.
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 assumed that NAT4's role in histone H4/H2A N-terminal acetylation supports chromatin homeostasis and thus promotes longevity. However, the actual finding is that NAT4 is anti-longevity, meaning its deletion or loss likely extends lifespan. The model's mechanistic reasoning was plausible-sounding but ultimately incorrect in its conclusion - it assumed that maintaining chromatin silencing via histone acetylation would be beneficial for longevity, when in fact NAT4 activity appears to be detrimental to lifespan in yeast. The model had moderate confidence (0.62) but still got the direction wrong.
Raw API responses
solver
{
"reasoning": "NAT4 (NatD) is the N-terminal acetyltransferase responsible for co-translational Nα-acetylation of histones H4 and H2A at their N-terminal serine residues. This modification is a conserved epigenetic mark on the histone tail that influences chromatin compaction and gene silencing. Proper N-terminal acetylation of histone H4 is linked to maintenance of heterochromatin structure and transcriptional regulation, processes critical for genomic stability and silencing of repetitive elements during aging. Loss of histone H4 Nα-acetylation disrupts chromatin integrity and has been associated with reduced replicative lifespan in yeast, as chromatin-based silencing (e.g., at rDNA and telomeres) is a key determinant of yeast longevity. Thus, NAT4's normal function in maintaining the histone H4/H2A epigenetic acetylation mark supports chromatin homeostasis and opposes age-associated epigenetic drift.",
"confidence": 0.62,
"key_pathways": [
"histone N-terminal acetylation (NatD/NAT4)",
"chromatin silencing and heterochromatin maintenance",
"epigenetic regulation of replicative lifespan"
],
"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 assumed that NAT4's role in histone H4/H2A N-terminal acetylation supports chromatin homeostasis and thus promotes longevity. However, the actual finding is that NAT4 is anti-longevity, meaning its deletion or loss likely extends lifespan. The model's mechanistic reasoning was plausible-sounding but ultimately incorrect in its conclusion - it assumed that maintaining chromatin silencing via histone acetylation would be beneficial for longevity, when in fact NAT4 activity appears to be detrimental to lifespan in yeast. 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": 2,
"ground_truth_questionable": false
}