{"gene":"TG_318470","gene_symbol":"AP2IV4","run_date":"2026-09-10T21:09:19","timeline":{"discoveries":[{"year":2018,"finding":"AP2IV-4 is a nuclear transcriptional repressor dynamically expressed in late S phase through mitosis/cytokinesis of the tachyzoite cell cycle. Deletion of the AP2IV-4 locus resulted in the aberrant expression of bradyzoite-specific proteins (BPK1, MCP4, CST1, SRS9) in replicating tachyzoites, establishing AP2IV-4 as a repressor of bradyzoite antigen expression during acute infection.","method":"Gene deletion (KO), immunofluorescence for nuclear localization, Western blot for protein expression timing, transcriptomic/protein analysis of bradyzoite-specific antigens in tachyzoites lacking AP2IV-4","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean gene deletion with defined molecular phenotype (specific bradyzoite antigens derepressed), protein localization and cell-cycle expression timing established, functional consequence validated in vivo","pmids":["29718996"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2018,"finding":"In the murine animal model, misexpression of bradyzoite antigens in tachyzoites lacking AP2IV-4 elicited a potent inflammatory monocyte immune response that eliminated the parasite and prevented tissue cyst formation in mouse brain tissue, demonstrating that AP2IV-4-mediated suppression of bradyzoite antigens is required for Toxoplasma to establish chronic infection in an immune-competent host.","method":"Mouse infection model with AP2IV-4 knockout parasites, immunological readouts (inflammatory monocyte response), brain cyst burden quantification","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with defined immunological and cyst-burden phenotype, mechanistically linked to derepression of bradyzoite antigens by AP2IV-4 deletion","pmids":["29718996"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2010,"finding":"AP2IV-4 protein expression peaks sharply during the tachyzoite cell cycle in a timeframe consistent with its mRNA pattern, suggesting that mechanisms responsible for the timing of protein delivery may be mediated by AP2 domain promoter recognition specificities. AP2IV-4 was identified as one of ~24 AP2 transcription factors forming a series through the tachyzoite cycle.","method":"Genome-wide cell cycle transcriptome analysis, protein expression profiling across tachyzoite cell cycle stages","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell-cycle-resolved transcriptomic and proteomic profiling across multiple AP2 factors, but no direct functional perturbation of AP2IV-4 specifically in this study","pmids":["20865045"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"AP2IV-4 is a nuclear ApiAP2 transcriptional repressor expressed during late S phase through mitosis/cytokinesis of the tachyzoite cell cycle that directly suppresses the expression of bradyzoite-specific antigens (including BPK1, MCP4, CST1, and SRS9) in replicating tachyzoites; its deletion causes premature bradyzoite antigen expression, triggering a host monocyte immune response that eliminates the parasite and prevents chronic brain cyst formation in mice."},"narrative":{"mechanistic_narrative":"AP2IV-4 is a nuclear ApiAP2 transcriptional repressor that enforces the tachyzoite gene expression program of Toxoplasma gondii by suppressing bradyzoite-specific antigens during acute infection [PMID:29718996]. It is one of a series of AP2 factors expressed in a cell-cycle-resolved manner, with protein levels peaking sharply from late S phase through mitosis/cytokinesis of the tachyzoite cycle [PMID:29718996, PMID:20865045]. Deletion of the locus derepresses bradyzoite-stage proteins (BPK1, MCP4, CST1, SRS9) in replicating tachyzoites, identifying these antigens as targets of AP2IV-4-mediated repression [PMID:29718996]. This repression is required for chronic infection: in an immune-competent murine model, premature misexpression of bradyzoite antigens in AP2IV-4 knockout parasites elicits an inflammatory monocyte response that clears the parasite and blocks brain tissue cyst formation [PMID:29718996]. The direct promoter targets bound by the AP2 domain and the mechanism of its stage-specific action have not been characterized beyond these findings in the available corpus.","teleology":[{"year":2010,"claim":"Before any function was assigned, it was unknown whether AP2IV-4 was regulated in a cell-cycle-dependent manner; profiling placed it within a temporally ordered series of AP2 factors, framing it as a candidate stage/cycle-specific transcription factor.","evidence":"Genome-wide cell cycle transcriptome and protein expression profiling across tachyzoite stages","pmids":["20865045"],"confidence":"Medium","gaps":["No direct functional perturbation of AP2IV-4 in this study","Promoter targets and DNA-binding specificity not defined","Repressor versus activator role not established"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2018,"claim":"It was unknown what genes AP2IV-4 controlled; gene deletion showed it represses bradyzoite-specific antigens in replicating tachyzoites, establishing it as a repressor that maintains the acute-stage program.","evidence":"Gene deletion with immunofluorescence for nuclear localization, cell-cycle expression timing, and analysis of bradyzoite antigen derepression (BPK1, MCP4, CST1, SRS9)","pmids":["29718996"],"confidence":"High","gaps":["Direct promoter binding of the AP2 domain to these target genes not demonstrated","Co-repressor partners or chromatin machinery not identified","Mechanism linking cell-cycle timing to target repression unresolved"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2018,"claim":"It was unknown whether bradyzoite antigen repression by AP2IV-4 mattered for infection outcome; in vivo knockout showed derepression triggers an inflammatory monocyte response that clears the parasite and prevents cyst formation, establishing AP2IV-4-mediated suppression as required for chronic infection.","evidence":"Mouse infection with AP2IV-4 knockout parasites, inflammatory monocyte readouts, and brain cyst burden quantification","pmids":["29718996"],"confidence":"High","gaps":["Which specific derepressed antigen(s) drive the immune clearance not resolved","Behavior across parasite strains not addressed","Role in natural (non-murine) hosts unknown"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":null,"claim":"Whether AP2IV-4 binds its bradyzoite target promoters directly and what co-factors or chromatin machinery mediate repression remains open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct DNA-binding/ChIP data linking AP2IV-4 to target promoters in the corpus","No identified interacting repressor complex","Mechanistic coupling of cell-cycle expression timing to repression not established"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":["Represses bradyzoite-specific antigens BPK1, MCP4, CST1, and SRS9 in replicating tachyzoites [#0]","Protein expression peaks from late S phase through mitosis/cytokinesis of the tachyzoite cell cycle [#0, #2]","One of ~24 ApiAP2 transcription factors forming a temporal series through the tachyzoite cycle [#2]","Suppression of bradyzoite antigens required to avoid inflammatory monocyte-mediated clearance and to permit chronic brain cyst formation [#1]"]},"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":"29718996","id":"PMC_29718996","title":"Transcriptional repression by ApiAP2 factors is central to chronic toxoplasmosis.","date":"2018","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/29718996","citation_count":77,"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":"19146987","id":"PMC_19146987","title":"Repeated secondary loss of adaptin complex genes in the Apicomplexa.","date":"2008","source":"Parasitology international","url":"https://pubmed.ncbi.nlm.nih.gov/19146987","citation_count":36,"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":"18983845","id":"PMC_18983845","title":"New eukaryotic systematics: a phylogenetic perspective of developmental gene expression in the Apicomplexa.","date":"2008","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/18983845","citation_count":12,"is_preprint":false},{"pmid":"39690155","id":"PMC_39690155","title":"Apicomplexan mitoribosome from highly fragmented rRNAs to a functional machine.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39690155","citation_count":9,"is_preprint":false},{"pmid":"36178892","id":"PMC_36178892","title":"Genomic insights into host and parasite interactions during intracellular infection by Toxoplasma gondii.","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/36178892","citation_count":2,"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":19678,"output_tokens":1015,"usd":0.03713,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5954,"output_tokens":2134,"usd":0.04156,"stage2_stop_reason":"end_turn"},"total_usd":0.07869,"stage1_batch_id":"msgbatch_01S6GjoYQm8LTPUsdhASdqag","stage2_batch_id":"msgbatch_01VX63RTMdBJqsG6gQMqoCjz","note":"batch pricing = 50% of standard","corrective_rerun":"2026-09-10 wrong-gene rerun (round-4 rules)","corrective_reason":"paper list: removed papers about other genes"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"AP2IV-4 is a nuclear transcriptional repressor dynamically expressed in late S phase through mitosis/cytokinesis of the tachyzoite cell cycle. Deletion of the AP2IV-4 locus resulted in the aberrant expression of bradyzoite-specific proteins (BPK1, MCP4, CST1, SRS9) in replicating tachyzoites, establishing AP2IV-4 as a repressor of bradyzoite antigen expression during acute infection.\",\n      \"method\": \"Gene deletion (KO), immunofluorescence for nuclear localization, Western blot for protein expression timing, transcriptomic/protein analysis of bradyzoite-specific antigens in tachyzoites lacking AP2IV-4\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean gene deletion with defined molecular phenotype (specific bradyzoite antigens derepressed), protein localization and cell-cycle expression timing established, functional consequence validated in vivo\",\n      \"pmids\": [\"29718996\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In the murine animal model, misexpression of bradyzoite antigens in tachyzoites lacking AP2IV-4 elicited a potent inflammatory monocyte immune response that eliminated the parasite and prevented tissue cyst formation in mouse brain tissue, demonstrating that AP2IV-4-mediated suppression of bradyzoite antigens is required for Toxoplasma to establish chronic infection in an immune-competent host.\",\n      \"method\": \"Mouse infection model with AP2IV-4 knockout parasites, immunological readouts (inflammatory monocyte response), brain cyst burden quantification\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with defined immunological and cyst-burden phenotype, mechanistically linked to derepression of bradyzoite antigens by AP2IV-4 deletion\",\n      \"pmids\": [\"29718996\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AP2IV-4 protein expression peaks sharply during the tachyzoite cell cycle in a timeframe consistent with its mRNA pattern, suggesting that mechanisms responsible for the timing of protein delivery may be mediated by AP2 domain promoter recognition specificities. AP2IV-4 was identified as one of ~24 AP2 transcription factors forming a series through the tachyzoite cycle.\",\n      \"method\": \"Genome-wide cell cycle transcriptome analysis, protein expression profiling across tachyzoite cell cycle stages\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-cycle-resolved transcriptomic and proteomic profiling across multiple AP2 factors, but no direct functional perturbation of AP2IV-4 specifically in this study\",\n      \"pmids\": [\"20865045\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"AP2IV-4 is a nuclear ApiAP2 transcriptional repressor expressed during late S phase through mitosis/cytokinesis of the tachyzoite cell cycle that directly suppresses the expression of bradyzoite-specific antigens (including BPK1, MCP4, CST1, and SRS9) in replicating tachyzoites; its deletion causes premature bradyzoite antigen expression, triggering a host monocyte immune response that eliminates the parasite and prevents chronic brain cyst formation in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AP2IV-4 is a nuclear ApiAP2 transcriptional repressor that enforces the tachyzoite gene expression program of Toxoplasma gondii by suppressing bradyzoite-specific antigens during acute infection [#0]. It is one of a series of AP2 factors expressed in a cell-cycle-resolved manner, with protein levels peaking sharply from late S phase through mitosis/cytokinesis of the tachyzoite cycle [#0, #2]. Deletion of the locus derepresses bradyzoite-stage proteins (BPK1, MCP4, CST1, SRS9) in replicating tachyzoites, identifying these antigens as targets of AP2IV-4-mediated repression [#0]. This repression is required for chronic infection: in an immune-competent murine model, premature misexpression of bradyzoite antigens in AP2IV-4 knockout parasites elicits an inflammatory monocyte response that clears the parasite and blocks brain tissue cyst formation [#1]. The direct promoter targets bound by the AP2 domain and the mechanism of its stage-specific action have not been characterized beyond these findings in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Before any function was assigned, it was unknown whether AP2IV-4 was regulated in a cell-cycle-dependent manner; profiling placed it within a temporally ordered series of AP2 factors, framing it as a candidate stage/cycle-specific transcription factor.\",\n      \"evidence\": \"Genome-wide cell cycle transcriptome and protein expression profiling across tachyzoite stages\",\n      \"pmids\": [\"20865045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct functional perturbation of AP2IV-4 in this study\",\n        \"Promoter targets and DNA-binding specificity not defined\",\n        \"Repressor versus activator role not established\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"It was unknown what genes AP2IV-4 controlled; gene deletion showed it represses bradyzoite-specific antigens in replicating tachyzoites, establishing it as a repressor that maintains the acute-stage program.\",\n      \"evidence\": \"Gene deletion with immunofluorescence for nuclear localization, cell-cycle expression timing, and analysis of bradyzoite antigen derepression (BPK1, MCP4, CST1, SRS9)\",\n      \"pmids\": [\"29718996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct promoter binding of the AP2 domain to these target genes not demonstrated\",\n        \"Co-repressor partners or chromatin machinery not identified\",\n        \"Mechanism linking cell-cycle timing to target repression unresolved\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"It was unknown whether bradyzoite antigen repression by AP2IV-4 mattered for infection outcome; in vivo knockout showed derepression triggers an inflammatory monocyte response that clears the parasite and prevents cyst formation, establishing AP2IV-4-mediated suppression as required for chronic infection.\",\n      \"evidence\": \"Mouse infection with AP2IV-4 knockout parasites, inflammatory monocyte readouts, and brain cyst burden quantification\",\n      \"pmids\": [\"29718996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which specific derepressed antigen(s) drive the immune clearance not resolved\",\n        \"Behavior across parasite strains not addressed\",\n        \"Role in natural (non-murine) hosts unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether AP2IV-4 binds its bradyzoite target promoters directly and what co-factors or chromatin machinery mediate repression remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct DNA-binding/ChIP data linking AP2IV-4 to target promoters in the corpus\",\n        \"No identified interacting repressor complex\",\n        \"Mechanistic coupling of cell-cycle expression timing to repression not established\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001217\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [0, 2], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006355\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"Represses bradyzoite-specific antigens BPK1, MCP4, CST1, and SRS9 in replicating tachyzoites [#0]\",\n      \"Protein expression peaks from late S phase through mitosis/cytokinesis of the tachyzoite cell cycle [#0, #2]\",\n      \"One of ~24 ApiAP2 transcription factors forming a temporal series through the tachyzoite cycle [#2]\",\n      \"Suppression of bradyzoite antigens required to avoid inflammatory monocyte-mediated clearance and to permit chronic brain cyst formation [#1]\"\n    ]\n  },\n  \"strain_conflicts\": []\n}","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_318470","name":"AP2IV4","product":"AP2 domain transcription factor AP2IV-4","uniprot_acc":"S8FCP8","chromosome":"TGME49_chrIV","start_pos":1300392},{"strain":"GT1","gene_id":"TGGT1_318470","name":null,"product":"AP2 domain transcription factor AP2IV-4","uniprot_acc":null,"chromosome":"TGGT1_chrIV","start_pos":1243471},{"strain":"RH88","gene_id":"TGRH88_008090","name":null,"product":"AP2 domain transcription factor AP2IV-4","uniprot_acc":null,"chromosome":"CM023085","start_pos":1323893},{"strain":"VEG","gene_id":"TGVEG_318470","name":null,"product":"AP2 domain transcription factor AP2IV-4","uniprot_acc":"V4ZBE8","chromosome":"TGVEG_chrIV","start_pos":1311375}]}