{"gene":"PF3D7_1008000","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":2014,"finding":"PfHda2 (PF3D7_1008000) functions as a global transcriptional silencer of virulence-associated var genes in P. falciparum asexual stages; depletion of PfHda2 leads to dysregulated (upregulated) expression of var genes, establishing its role as an epigenetic repressor of antigenic variation.","method":"Conditional depletion (loss-of-function) of PfHda2 with transcriptional readout of var gene expression","journal":"Cell host & microbe","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined molecular phenotype (var gene derepression), single lab, single primary method","pmids":["25121747"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"PfHda2 (PF3D7_1008000) represses expression of PfAP2-g, the master transcription factor controlling sexual conversion; depletion of PfHda2 causes upregulation of PfAP2-g and a consequent increase in gametocytogenesis, placing PfHda2 upstream of PfAP2-g in the sexual-conversion pathway.","method":"Conditional depletion of PfHda2 with measurement of PfAP2-g transcript levels and gametocyte conversion rates","journal":"Cell host & microbe","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by loss-of-function with defined downstream molecular and cellular phenotypes, single lab","pmids":["25121747"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"PfHda2 (PF3D7_1008000) is an essential nuclear gene in P. falciparum, localizing to the nucleus where it carries out its silencing function.","method":"Characterization of the nuclear gene product; loss-of-function depletion experiments confirming essentiality","journal":"Cell host & microbe","confidence":"Low","confidence_rationale":"Tier 3 / Weak — nuclear localization stated from characterization, single lab, abstract does not detail direct localization imaging methods","pmids":["25121747"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfHda2 (PF3D7_1008000) is an essential nuclear histone deacetylase in P. falciparum that acts as a global epigenetic silencer of virulence-associated var genes and represses the sexual-conversion transcription factor PfAP2-g, thereby coordinately controlling antigenic variation and the rate of gametocytogenesis."},"narrative":{"mechanistic_narrative":"PF3D7_1008000 (HDA2) is a nuclear histone deacetylase that acts as a global epigenetic silencer coordinating antigenic variation and sexual commitment in Plasmodium falciparum asexual stages [PMID:25121747]. Conditional depletion derepresses the virulence-associated var gene family, establishing HDA2 as a repressor of antigenic variation [PMID:25121747], and simultaneously upregulates the master sexual-conversion transcription factor PfAP2-g, increasing gametocytogenesis and placing HDA2 upstream of PfAP2-g in the sexual-conversion pathway [PMID:25121747]. Beyond this silencing role, the molecular details of HDA2 — its enzymatic targets, chromatin recruitment, and any complex partners — have not been characterized in the available corpus.","teleology":[{"year":2014,"claim":"It was unknown what enforces silencing of the clonally variant var gene family; loss-of-function of HDA2 showed that it is required to keep var genes repressed, establishing it as a global epigenetic silencer of antigenic variation.","evidence":"Conditional depletion of PfHda2 with transcriptional readout of var gene expression in P. falciparum asexual stages","pmids":["25121747"],"confidence":"Medium","gaps":["No direct demonstration of histone deacetylase enzymatic activity or its acetyl-lysine substrates for this gene","Chromatin recruitment mechanism to var loci not defined","No identification of complex partners"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"It was unknown what restrains the rate of sexual conversion upstream of PfAP2-g; HDA2 depletion upregulated PfAP2-g and increased gametocytogenesis, placing HDA2 as an upstream repressor of the sexual-commitment switch.","evidence":"Conditional depletion of PfHda2 with measurement of PfAP2-g transcript levels and gametocyte conversion rates in P. falciparum","pmids":["25121747"],"confidence":"Medium","gaps":["Whether HDA2 acts directly at the pfap2-g locus versus indirectly is not resolved","No mechanistic link established between var silencing and PfAP2-g repression by this gene"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"The subcellular compartment and dispensability of HDA2 were unknown; characterization indicated a nuclear, essential gene product consistent with a chromatin-silencing role.","evidence":"Characterization of the nuclear gene product and loss-of-function depletion in P. falciparum","pmids":["25121747"],"confidence":"Low","gaps":["Nuclear localization stated without detailed direct imaging methodology in the abstract","Essentiality reported from a single lab and single approach"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The biochemical basis of HDA2 silencing — direct deacetylase activity, histone substrates, target-locus recruitment, and any protein complex it operates within — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No enzymatic assay defining substrate specificity for this gene","No structural or interaction data","No mechanism explaining how one factor coordinately silences var genes and pfap2-g"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":["Global transcriptional silencer of virulence-associated var genes (antigenic variation) [#0]","Represses the master sexual-conversion transcription factor PfAP2-g, acting upstream to limit gametocytogenesis [#1]","Essential nuclear gene in P. falciparum [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"25121747","id":"PMC_25121747","title":"A Plasmodium falciparum histone deacetylase regulates antigenic variation and gametocyte conversion.","date":"2014","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/25121747","citation_count":174,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["histone deacetylase 2","PfHDA2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"26595183","id":"PMC_26595183","title":"Homology modeling of parasite histone deacetylases to guide the structure-based design of selective inhibitors.","date":"2015","source":"Journal of molecular graphics & modelling","url":"https://pubmed.ncbi.nlm.nih.gov/26595183","citation_count":39,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23123170","id":"PMC_23123170","title":"A Plasmodium multi-domain protein possesses multiple inositol phosphate kinase activities.","date":"2012","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/23123170","citation_count":5,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4020,"output_tokens":841,"usd":0.012337,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5488,"output_tokens":1584,"usd":0.03352,"stage2_stop_reason":"end_turn"},"total_usd":0.045857,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"PfHda2 (PF3D7_1008000) functions as a global transcriptional silencer of virulence-associated var genes in P. falciparum asexual stages; depletion of PfHda2 leads to dysregulated (upregulated) expression of var genes, establishing its role as an epigenetic repressor of antigenic variation.\",\n      \"method\": \"Conditional depletion (loss-of-function) of PfHda2 with transcriptional readout of var gene expression\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined molecular phenotype (var gene derepression), single lab, single primary method\",\n      \"pmids\": [\"25121747\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PfHda2 (PF3D7_1008000) represses expression of PfAP2-g, the master transcription factor controlling sexual conversion; depletion of PfHda2 causes upregulation of PfAP2-g and a consequent increase in gametocytogenesis, placing PfHda2 upstream of PfAP2-g in the sexual-conversion pathway.\",\n      \"method\": \"Conditional depletion of PfHda2 with measurement of PfAP2-g transcript levels and gametocyte conversion rates\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by loss-of-function with defined downstream molecular and cellular phenotypes, single lab\",\n      \"pmids\": [\"25121747\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PfHda2 (PF3D7_1008000) is an essential nuclear gene in P. falciparum, localizing to the nucleus where it carries out its silencing function.\",\n      \"method\": \"Characterization of the nuclear gene product; loss-of-function depletion experiments confirming essentiality\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — nuclear localization stated from characterization, single lab, abstract does not detail direct localization imaging methods\",\n      \"pmids\": [\"25121747\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PfHda2 (PF3D7_1008000) is an essential nuclear histone deacetylase in P. falciparum that acts as a global epigenetic silencer of virulence-associated var genes and represses the sexual-conversion transcription factor PfAP2-g, thereby coordinately controlling antigenic variation and the rate of gametocytogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1008000 (HDA2) is a nuclear histone deacetylase that acts as a global epigenetic silencer coordinating antigenic variation and sexual commitment in Plasmodium falciparum asexual stages [#0, #1]. Conditional depletion derepresses the virulence-associated var gene family, establishing HDA2 as a repressor of antigenic variation [#0], and simultaneously upregulates the master sexual-conversion transcription factor PfAP2-g, increasing gametocytogenesis and placing HDA2 upstream of PfAP2-g in the sexual-conversion pathway [#1]. Beyond this silencing role, the molecular details of HDA2 — its enzymatic targets, chromatin recruitment, and any complex partners — have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"It was unknown what enforces silencing of the clonally variant var gene family; loss-of-function of HDA2 showed that it is required to keep var genes repressed, establishing it as a global epigenetic silencer of antigenic variation.\",\n      \"evidence\": \"Conditional depletion of PfHda2 with transcriptional readout of var gene expression in P. falciparum asexual stages\",\n      \"pmids\": [\"25121747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct demonstration of histone deacetylase enzymatic activity or its acetyl-lysine substrates for this gene\",\n        \"Chromatin recruitment mechanism to var loci not defined\",\n        \"No identification of complex partners\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"It was unknown what restrains the rate of sexual conversion upstream of PfAP2-g; HDA2 depletion upregulated PfAP2-g and increased gametocytogenesis, placing HDA2 as an upstream repressor of the sexual-commitment switch.\",\n      \"evidence\": \"Conditional depletion of PfHda2 with measurement of PfAP2-g transcript levels and gametocyte conversion rates in P. falciparum\",\n      \"pmids\": [\"25121747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether HDA2 acts directly at the pfap2-g locus versus indirectly is not resolved\",\n        \"No mechanistic link established between var silencing and PfAP2-g repression by this gene\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The subcellular compartment and dispensability of HDA2 were unknown; characterization indicated a nuclear, essential gene product consistent with a chromatin-silencing role.\",\n      \"evidence\": \"Characterization of the nuclear gene product and loss-of-function depletion in P. falciparum\",\n      \"pmids\": [\"25121747\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Nuclear localization stated without detailed direct imaging methodology in the abstract\",\n        \"Essentiality reported from a single lab and single approach\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical basis of HDA2 silencing — direct deacetylase activity, histone substrates, target-locus recruitment, and any protein complex it operates within — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No enzymatic assay defining substrate specificity for this gene\",\n        \"No structural or interaction data\",\n        \"No mechanism explaining how one factor coordinately silences var genes and pfap2-g\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"Global transcriptional silencer of virulence-associated var genes (antigenic variation) [#0]\",\n      \"Represses the master sexual-conversion transcription factor PfAP2-g, acting upstream to limit gametocytogenesis [#1]\",\n      \"Essential nuclear gene in P. falciparum [#2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1008000","name":null,"product":"histone deacetylase 2","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1206200","name":null,"product":"histone deacetylase 2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0807000","name":null,"product":"histone deacetylase 2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"HDA2","evaluation":null}