{"gene":"TG_247700","gene_symbol":"AP2XII4","run_date":"2026-09-11T11:01:00","timeline":{"discoveries":[{"year":2019,"finding":"AP2XII-4 associates with GCN5b in a distinct transcriptional complex in Toxoplasma tachyzoites. Reciprocal co-immunoprecipitation of AP2XII-4 delineated its interactome, and together with the AP2IX-7-containing complex, suggests GCN5b is present in at least two distinct complexes characterized by different pairs of AP2 factors. This implicates AP2XII-4 in GCN5b-mediated epigenetic gene regulation.","method":"Co-immunoprecipitation (reciprocal Co-IP) under tachyzoite and bradyzoite-inducing conditions followed by mass spectrometry","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS identification, single lab, two orthogonal approaches (normal and bradyzoite induction conditions)","pmids":["31381949"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2010,"finding":"AP2XII-4 is one of ~24 AP2 transcription factors that form a series through the tachyzoite cell cycle, with successive sharp peaks of protein expression correlated with mRNA timing. Peak expression timing is consistent with a role mediated by AP2 domains with different promoter recognition specificities during coordinated cell cycle progression.","method":"Genome-wide cell cycle transcriptome profiling; protein expression timing analysis in dividing tachyzoites","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression profiling and timing correlation without direct functional perturbation of AP2XII-4 specifically","pmids":["20865045"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"AP2XII-4 (also annotated as TgAP2XI-4) is a nuclear ApiAP2 transcription factor in Toxoplasma gondii that directly binds a specific DNA motif via its AP2 domain, peaks in expression after cytokinesis in the tachyzoite cell cycle, and is required for tachyzoite-to-bradyzoite stage conversion and brain cyst formation in vivo; it also physically associates with the essential lysine acetyltransferase GCN5b in a distinct multi-subunit transcriptional complex and is subject to arginine monomethylation, implicating it in epigenetic regulation of parasite development."},"narrative":{"mechanistic_narrative":"AP2XII-4 is a nuclear ApiAP2 transcription factor in Toxoplasma gondii that is one of ~24 AP2 transcription factors forming a series through the tachyzoite cell cycle, with successive sharp peaks of protein expression correlated with mRNA timing, consistent with a role mediated by AP2 domains with different promoter recognition specificities during coordinated cell cycle progression [PMID:20865045]. It associates with the lysine acetyltransferase GCN5b in a distinct multi-subunit transcriptional complex; reciprocal co-immunoprecipitation of AP2XII-4 delineated its interactome, and together with the AP2IX-7-containing complex, suggests GCN5b is present in at least two distinct complexes characterized by different pairs of AP2 factors, implicating AP2XII-4 in GCN5b-mediated epigenetic gene regulation [PMID:31381949]. The precise DNA targets and the functional consequences of its GCN5b association have not been directly characterized in the available corpus.","teleology":[{"year":2010,"claim":"Before functional data existed, it was unknown whether AP2XII-4 participated in ordered cell-cycle gene control; expression profiling placed it within a series of AP2 factors peaking at successive cell-cycle points, framing it as a candidate stage-specific regulator.","evidence":"Genome-wide cell cycle transcriptome and protein expression timing analysis in dividing tachyzoites","pmids":["20865045"],"confidence":"Low","gaps":["Correlative timing only, no direct perturbation of AP2XII-4","No DNA target or binding motif established","Does not distinguish causal role from co-regulation"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2019,"claim":"It was unknown how AP2XII-4 exerts transcriptional effects at chromatin; reciprocal Co-IP/MS placed it in a distinct GCN5b-containing complex, linking it to acetyltransferase-mediated epigenetic regulation.","evidence":"Reciprocal co-immunoprecipitation with mass spectrometry under tachyzoite and bradyzoite-inducing conditions","pmids":["31381949"],"confidence":"Medium","gaps":["Functional consequence of GCN5b association for target gene acetylation not demonstrated","Full subunit composition and stoichiometry of the complex not resolved","Whether AP2XII-4 recruits GCN5b to specific promoters untested"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["GCN5b-containing transcriptional complex (with AP2XII-4)"],"partners":["GCN5B"],"other_free_text":["AP2XII-4 is annotated in some literature as TgAP2XI-4.","Peak protein expression occurs after cytokinesis in the tachyzoite cell cycle.","Required for tachyzoite-to-bradyzoite stage conversion and brain cyst formation in vivo (type II strain).","Subject to arginine monomethylation."]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"20865045","id":"PMC_20865045","title":"Coordinated progression through two subtranscriptomes underlies the tachyzoite cycle of Toxoplasma gondii.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20865045","citation_count":234,"is_preprint":false},{"pmid":"29932347","id":"PMC_29932347","title":"The Epigenome, Cell Cycle, and Development in Toxoplasma.","date":"2018","source":"Annual review of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29932347","citation_count":51,"is_preprint":false},{"pmid":"20657661","id":"PMC_20657661","title":"The construction and use of log-odds substitution scores for multiple sequence alignment.","date":"2010","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/20657661","citation_count":48,"is_preprint":false},{"pmid":"22486860","id":"PMC_22486860","title":"Cactin is essential for G1 progression in Toxoplasma gondii.","date":"2012","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22486860","citation_count":23,"is_preprint":false},{"pmid":"25393307","id":"PMC_25393307","title":"Distinct strains of Toxoplasma gondii feature divergent transcriptomes regardless of developmental stage.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25393307","citation_count":22,"is_preprint":false},{"pmid":"31381949","id":"PMC_31381949","title":"A novel GCN5b lysine acetyltransferase complex associates with distinct transcription factors in the protozoan parasite Toxoplasma gondii.","date":"2019","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/31381949","citation_count":20,"is_preprint":false},{"pmid":"42087241","id":"PMC_42087241","title":"Host-cell dependent epigenetic profiles associated with survival outcomes in T. gondii infection.","date":"2026","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/42087241","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12970,"output_tokens":1378,"usd":0.02979,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6406,"output_tokens":2616,"usd":0.048715,"stage2_stop_reason":"end_turn"},"total_usd":0.082032,"stage1_batch_id":"msgbatch_01TEPNZ4MCzJ7xtsNwosiDRk","stage2_batch_id":"msgbatch_01FQShM7n1sfCr4pWTDShmki","note":"batch pricing = 50% of standard","corrective_rerun":"2026-09-10 wrong-gene rerun (round-4 rules)","corrective_reason":"summary amended","hand_review_patch":"2026-09-11 AK hand-review verdicts (handoff/tools_2026-09-11/patch)","hand_review_verdict":"edit"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"TgAP2XI-4 (note: the gene symbol AP2XII-4 appears as an alias; the paper uses 'TgAP2XI-4') protein localizes to the parasite nucleus throughout the tachyzoite life cycle in vitro, with peak expression occurring after cytokinesis. A recombinant protein encompassing its AP2 domain specifically binds a DNA motif in gel retardation assays. Knockout of TgAP2XI-4 in type I and type II strains reveals its role in modulating expression and promoter activity of genes involved in tachyzoite-to-bradyzoite stage conversion, and type II KO mutants show drastically reduced brain cyst burden in mice.\",\n      \"method\": \"Gel retardation assay (EMSA) for DNA binding; nuclear localization by direct imaging; gene knockout in type I (RH) and type II strains; promoter activity assays; mouse infection model for cyst burden\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EMSA, KO in two strains, promoter assay, in vivo cyst burden), replicated across strain types\",\n      \"pmids\": [\"23240624\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"RH\"},\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"type II\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AP2XII-4 associates with GCN5b in a distinct transcriptional complex in Toxoplasma tachyzoites. Reciprocal co-immunoprecipitation of AP2XII-4 delineated its interactome, and together with the AP2IX-7-containing complex, suggests GCN5b is present in at least two distinct complexes characterized by different pairs of AP2 factors. This implicates AP2XII-4 in GCN5b-mediated epigenetic gene regulation.\",\n      \"method\": \"Co-immunoprecipitation (reciprocal Co-IP) under tachyzoite and bradyzoite-inducing conditions followed by mass spectrometry\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS identification, single lab, two orthogonal approaches (normal and bradyzoite induction conditions)\",\n      \"pmids\": [\"31381949\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AP2XII-4 is one of ~24 AP2 transcription factors that form a series through the tachyzoite cell cycle, with successive sharp peaks of protein expression correlated with mRNA timing. Peak expression timing is consistent with a role mediated by AP2 domains with different promoter recognition specificities during coordinated cell cycle progression.\",\n      \"method\": \"Genome-wide cell cycle transcriptome profiling; protein expression timing analysis in dividing tachyzoites\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression profiling and timing correlation without direct functional perturbation of AP2XII-4 specifically\",\n      \"pmids\": [\"20865045\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AP2XII-4 (an ApiAP2 transcription factor) is detected among the arginine monomethylated proteins in Toxoplasma gondii, identified by affinity purification with anti-monomethylarginine antibodies followed by mass spectrometry, suggesting it is a substrate of protein arginine methyltransferases including PRMT1.\",\n      \"method\": \"Affinity purification with anti-MMA antibodies followed by mass spectrometry; comparative proteomics with PRMT1 knockdown\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single proteomics screen identifying AP2XII-4 as a post-translational modification substrate, no direct functional follow-up on this specific factor\",\n      \"pmids\": [\"28143887\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"AP2XII-4 (also annotated as TgAP2XI-4) is a nuclear ApiAP2 transcription factor in Toxoplasma gondii that directly binds a specific DNA motif via its AP2 domain, peaks in expression after cytokinesis in the tachyzoite cell cycle, and is required for tachyzoite-to-bradyzoite stage conversion and brain cyst formation in vivo; it also physically associates with the essential lysine acetyltransferase GCN5b in a distinct multi-subunit transcriptional complex and is subject to arginine monomethylation, implicating it in epigenetic regulation of parasite development.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AP2XII-4 (also annotated TgAP2XI-4) is a nuclear ApiAP2 transcription factor in Toxoplasma gondii that couples cell-cycle-timed gene expression to developmental stage conversion [#0]. It localizes to the tachyzoite nucleus throughout the cell cycle with peak expression after cytokinesis, and a recombinant fragment spanning its AP2 domain binds a specific DNA motif in vitro, establishing it as a sequence-specific DNA-binding regulator [#0]. Knockout in type I and type II strains alters the expression and promoter activity of genes governing the tachyzoite-to-bradyzoite transition, and type II mutants show drastically reduced brain cyst burden in mice, defining AP2XII-4 as a regulator of bradyzoite differentiation and cyst formation in vivo [#0]. Mechanistically, it acts within a chromatin-modifying context: it associates with the lysine acetyltransferase GCN5b in a distinct multi-subunit transcriptional complex [#1] and is itself a substrate of arginine monomethylation [#3], linking its transcriptional activity to epigenetic regulation. The precise DNA targets, the functional consequences of its GCN5b association, and the role of its arginine methylation have not been directly characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Before functional data existed, it was unknown whether AP2XII-4 participated in ordered cell-cycle gene control; expression profiling placed it within a series of AP2 factors peaking at successive cell-cycle points, framing it as a candidate stage-specific regulator.\",\n      \"evidence\": \"Genome-wide cell cycle transcriptome and protein expression timing analysis in dividing tachyzoites\",\n      \"pmids\": [\"20865045\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative timing only, no direct perturbation of AP2XII-4\", \"No DNA target or binding motif established\", \"Does not distinguish causal role from co-regulation\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"It was unknown whether AP2XII-4 was a bona fide DNA-binding transcription factor with a developmental function; direct binding, localization, knockout, and in vivo assays showed it binds a specific DNA motif, localizes to the nucleus, and is required for normal bradyzoite gene expression and brain cyst formation.\",\n      \"evidence\": \"EMSA for DNA binding, nuclear imaging, knockout in RH (type I) and type II strains, promoter assays, and mouse cyst burden model\",\n      \"pmids\": [\"23240624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide direct target genes not mapped\", \"Mechanism of activation versus repression at target promoters unresolved\", \"Cofactor requirements for DNA binding in vivo unknown\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"RH\"}, {\"species\": \"Toxoplasma gondii\", \"strain\": \"type II\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"It was unknown whether AP2XII-4 activity is post-translationally regulated; a monomethylarginine proteomics screen identified it as an arginine-monomethylated protein, implicating PRMT1-dependent methylation in its regulation.\",\n      \"evidence\": \"Affinity purification with anti-monomethylarginine antibodies plus mass spectrometry and comparative proteomics under PRMT1 knockdown\",\n      \"pmids\": [\"28143887\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single proteomics screen without functional follow-up on AP2XII-4\", \"Methylation sites and their effect on DNA binding or complex assembly not defined\", \"Direct enzyme-substrate relationship with PRMT1 not validated\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"It was unknown how AP2XII-4 exerts transcriptional effects at chromatin; reciprocal Co-IP/MS placed it in a distinct GCN5b-containing complex, linking it to acetyltransferase-mediated epigenetic regulation.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation with mass spectrometry under tachyzoite and bradyzoite-inducing conditions\",\n      \"pmids\": [\"31381949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of GCN5b association for target gene acetylation not demonstrated\", \"Full subunit composition and stoichiometry of the complex not resolved\", \"Whether AP2XII-4 recruits GCN5b to specific promoters untested\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct genome-wide DNA targets of AP2XII-4, the functional role of its GCN5b association at those targets, and how arginine methylation modulates its activity remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ChIP-seq or in vivo occupancy map\", \"Causal link between complex membership and bradyzoite gene control not established\", \"Regulatory input of PTMs on function untested\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"RH\"}, {\"species\": \"Toxoplasma gondii\", \"strain\": \"type II\"}]},\n      {\"term_id\": \"GO:0043565\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"RH\"}, {\"species\": \"Toxoplasma gondii\", \"strain\": \"type II\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"RH\"}, {\"species\": \"Toxoplasma gondii\", \"strain\": \"type II\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006355\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0030154\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"type II\"}]}\n    ],\n    \"complexes\": [\"GCN5b-containing transcriptional complex (with AP2XII-4)\"],\n    \"partners\": [\"GCN5b\", \"PRMT1 (as monomethylarginine-modifying enzyme)\"],\n    \"other_free_text\": [\n      \"AP2XII-4 is annotated in some literature as TgAP2XI-4.\",\n      \"Peak protein expression occurs after cytokinesis in the tachyzoite cell cycle.\",\n      \"Required for tachyzoite-to-bradyzoite stage conversion and brain cyst formation in vivo (type II strain).\",\n      \"Subject to arginine monomethylation.\"\n    ]\n  },\n  \"strain_conflicts\": []\n}\n```","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_247700","name":"AP2XII4","product":"AP2 domain transcription factor AP2XII-4","uniprot_acc":"A0A125YU40","chromosome":"TGME49_chrXII","start_pos":3507570},{"strain":"GT1","gene_id":"TGGT1_247700","name":null,"product":"AP2 domain transcription factor AP2XII-4","uniprot_acc":null,"chromosome":"TGGT1_chrXII","start_pos":3439195},{"strain":"RH88","gene_id":"TGRH88_061790","name":null,"product":"AP2 domain transcription factor AP2XII-4","uniprot_acc":null,"chromosome":"CM023093","start_pos":3560665},{"strain":"VEG","gene_id":"TGVEG_247700","name":null,"product":"AP2 domain transcription factor AP2XII-4","uniprot_acc":"B6KH14","chromosome":"TGVEG_chrXII","start_pos":3478353}]}