{"gene":"TG_227290","gene_symbol":"HDAC3","run_date":"2026-09-08T11:06:46","timeline":{"discoveries":[{"year":2009,"finding":"TgHDAC3 was identified as the direct molecular target of the cyclic tetrapeptide HDACi FR235222 in Toxoplasma tachyzoites; the conserved Apicomplexa-specific residue T99 in TgHDAC3 is critical for the drug's inhibitory activity, established by active-site mutagenesis showing that mutation of T99 abolishes FR235222 inhibition.","method":"Drug target identification via genetic/biochemical approach; active-site mutagenesis of TgHDAC3 T99; phenotypic rescue","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis identifying a specific catalytic residue required for inhibitor activity, single lab but multiple functional validations","pmids":["19349466"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2009,"finding":"Inhibition of TgHDAC3 by FR235222 induces differentiation of tachyzoites (replicative stage) into bradyzoites (non-replicative stage) and influences the expression of approximately 370 genes, a third of which are stage-specifically expressed, establishing TgHDAC3 as a central regulator of gene expression and stage conversion.","method":"HDACi treatment (FR235222) followed by transcriptome analysis and stage conversion assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with specific target validation plus genome-wide transcriptome analysis, single lab with multiple orthogonal readouts","pmids":["19349466"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2010,"finding":"FR235222 targets TgHDAC3 in bradyzoites and cyst forms in vitro and ex vivo; structural knowledge of TgHDAC3 was used to rationally design new FR235222 derivative compounds with improved selectivity, confirming HDAC3 as the pharmacological target in both tachyzoite and bradyzoite stages.","method":"Ex vivo cyst treatment, fluorescent labeling, structure-guided medicinal chemistry, in vivo cyst infection assay in mice","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-guided drug design using TgHDAC3 as target, confirmed by ex vivo and in vivo efficacy, single lab","pmids":["20713670"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2020,"finding":"HDAC3 is recruited to chromatin at sexual-stage gene promoters by the MORC protein in complex with AP2 transcription factors, thereby restricting chromatin accessibility and repressing genes exclusively expressed during sexual stages; this positions HDAC3 as an effector within a MORC-AP2 transcriptional repressor complex.","method":"Co-immunoprecipitation, chromatin accessibility assays, conditional depletion of MORC, transcriptome analysis","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing the MORC-AP2-HDAC3 complex, conditional depletion with defined transcriptional phenotype, chromatin accessibility assays, replicated in subsequent studies","pmids":["32094587"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"finding":"AP2XII-1 and AP2XI-2 bind DNA as heterodimers at merozoite gene promoters in tachyzoites and recruit MORC and HDAC3, thereby limiting chromatin accessibility and repressing merozoite-specific transcription; depletion of both factors causes epigenetic rewiring and tachyzoite-to-merozoite transition.","method":"Conditional depletion, ChIP/CUT&Tag, chromatin accessibility (ATAC-seq), Co-immunoprecipitation, transcriptome analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, CUT&Tag, ATAC-seq, and conditional KO with defined stage-transition phenotype, replicated across peer-reviewed paper and preprint","pmids":["38093015"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"finding":"AP2XII-2 co-occupies genomic loci associated with sexually committed parasites together with HDAC3 and MORC, contributing to the repression of a subset of sexual-stage genes including AP2X-10 and AAH1, as demonstrated by CUT&Tag chromatin profiling and conditional depletion.","method":"CUT&Tag, conditional depletion, transcriptome analysis","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag and conditional KO showing co-occupancy and gene de-repression, single lab","pmids":["36786611"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"finding":"AP2XII-5 forms a nuclear complex with MORC and HDAC3 (as well as the novel protein AIP1) that suppresses developmentally regulated genes at tachyzoite stage; AP2XII-5 binds promoters of developmentally activated genes and recruits MORC and HDAC3 to repress their expression.","method":"Immunoprecipitation and mass spectrometry (complex identification), conditional depletion, transcriptome and chromatin binding assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identifying the complex, conditional depletion with defined transcriptional phenotype, single lab","pmids":["39716984"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"finding":"AP2XII-1 and AP2XI-2 target the MORC-HDAC3 complex to merozoite gene promoters; their disruption profoundly alters expression of merozoite-specific genes, with AP2XII-1 specifically binding a subset of ApiAP2 transcription factors including AP2XI-2, establishing a hierarchical ApiAP2 regulatory cascade upstream of HDAC3-mediated repression.","method":"Immunoprecipitation, mass spectrometry, conditional knockout, transcriptome analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS for complex identification, conditional KO with transcriptional phenotype, single lab","pmids":["38791568"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2025,"finding":"MORC and HDAC3 epistatically regulate BFD1 (a key bradyzoite regulator), placing the MORC/HDAC3 repressor complex upstream of BFD1 in the pathway controlling bradyzoite gene expression and chronic persistence.","method":"Genetic epistasis analysis, conditional depletion, transcriptome analysis","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by conditional depletions with transcriptional readouts, single lab","pmids":["40389644"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2025,"finding":"AP2X-1 associates with the HDAC3/MORC complex and co-occupies promoters of bradyzoite- and sexual stage-specific genes; loss of AP2X-1 leads to upregulation of these genes, chromatin decompaction at target loci, and induction of bradyzoite differentiation and sexual commitment, indicating AP2X-1 modulates HDAC3/MORC function to repress developmental gene expression.","method":"Co-immunoprecipitation (complex association), CUT&Tag chromatin profiling, ATAC-seq, conditional knockout, transcriptome analysis, single-cell sequencing","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, CUT&Tag, ATAC-seq, and conditional KO with multiple orthogonal readouts, single lab","pmids":["40823841"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"finding":"In tachyzoites, AP2XII-1 and AP2XI-2 bind merozoite gene promoters as heterodimers and recruit MORC and HDAC3 to restrict chromatin accessibility; this was confirmed independently in a preprint preceding the published Nature paper.","method":"Conditional depletion, CUT&Tag, ATAC-seq, Co-immunoprecipitation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint with multiple orthogonal methods, subsequently confirmed in the peer-reviewed publication (PMID 38093015)","pmids":["36711883"],"is_preprint":true,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"finding":"Pharmacological inhibition of HDAC3 with apicidin (a commercially available HDACi) in tachyzoites induces expression of sporozoite-specific genes including SporoSAG and LEA860, confirming HDAC3 actively represses oocyst/sporozoite-stage gene expression in tachyzoites.","method":"Drug inhibition (apicidin), immunofluorescence microscopy, immunoprecipitation, mass spectrometry","journal":"FEMS microbes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition of HDAC3 with stage-specific transcriptional and proteomic readouts, single lab","pmids":["39802703"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2007,"finding":"T. gondii expresses a Class I HDAC enzyme homologous to human HDAC3; hydroxamic acid HDACi compounds (SAHA, scriptaid, TSA) at nanomolar concentrations inhibit tachyzoite proliferation, while the Class III HDAC inhibitor nicotinamide had minimal anti-parasitic activity, functionally implicating Class I HDAC (HDAC3) in tachyzoite replication.","method":"In vitro anti-parasitic proliferation assay with selective HDAC inhibitors; sequence homology","journal":"The Journal of parasitology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological profiling without direct target validation, class-level inference only","pmids":["17626366"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":"RH"}]},{"year":2020,"finding":"Treatment with the HDAC inhibitor Tubastatin A (TST) led to increased histone H4 acetylation and decreased H3 acetylation, impaired endodyogeny (budding of daughter cells), caused centrosome dispersal, apicoplast division defects, mitochondrial membrane potential disruption, and IMC assembly failure; TST possibly inhibits HDAC3 and other HDACs involved in non-histone protein modification.","method":"Western blotting (histone acetylation), fluorescence and electron microscopy, mitochondrial membrane potential assay, in vitro proliferation assay","journal":"International journal for parasitology. Drugs and drug resistance","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibition without direct TgHDAC3 target confirmation; multiple HDACs potentially involved","pmids":["33360687"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":"RH; ME49"}]}],"current_model":"TgHDAC3 is a histone deacetylase whose catalytic activity (requiring the conserved T99 residue) maintains transcriptional repression of developmental-stage-specific genes by being recruited, as part of a MORC/AP2 transcription factor repressor complex, to the promoters of bradyzoite, merozoite, and sexual-stage genes in proliferating tachyzoites; inhibition or disruption of this complex de-represses these stage-specific gene programs, triggering irreversible stage conversion, and HDAC3 additionally functions epistatically upstream of the master bradyzoite regulator BFD1."},"narrative":{"mechanistic_narrative":"TgHDAC3 is a class I histone deacetylase in Toxoplasma gondii that acts as the central epigenetic enforcer of developmental-stage identity, maintaining transcriptional repression of stage-specific gene programs in proliferating tachyzoites [PMID:19349466]. It is the direct molecular target of the cyclic tetrapeptide inhibitor FR235222, and the Apicomplexa-specific active-site residue T99 is required for this inhibition, defining a druggable catalytic pocket distinct from host HDACs [PMID:19349466]. Pharmacological inhibition of TgHDAC3 de-represses roughly 370 genes—a third of them stage-specific—and drives conversion of replicative tachyzoites into non-replicative bradyzoites [PMID:19349466], and independently induces sporozoite-stage genes such as SporoSAG and LEA860 [PMID:39802703]. Mechanistically, HDAC3 does not act autonomously but is recruited to promoters of bradyzoite, merozoite, and sexual-stage genes as the effector of a MORC-scaffolded repressor complex, where sequence-specific ApiAP2 transcription factors—including AP2XII-1/AP2XI-2 heterodimers at merozoite loci, AP2XII-2, AP2XII-5, and AP2X-1—target the MORC-HDAC3 module to particular loci to restrict chromatin accessibility [PMID:32094587, PMID:38093015, PMID:39716984, PMID:40823841]. This forms a hierarchical ApiAP2 cascade upstream of HDAC3-mediated deacetylation [PMID:38791568], and the MORC/HDAC3 complex acts epistatically upstream of the master bradyzoite regulator BFD1 to control chronic-stage differentiation [PMID:40389644]. Disruption of this complex causes chromatin decompaction at target loci and irreversible stage conversion, making the pathway both a driver of parasite persistence and an antiparasitic drug target [PMID:38093015, PMID:40823841].","teleology":[{"year":2007,"claim":"Establishing that a Class I HDAC contributes to tachyzoite proliferation was the first step toward identifying a druggable chromatin regulator, addressing whether HDAC activity is required for parasite growth.","evidence":"In vitro anti-parasitic proliferation assays with class-selective HDAC inhibitors and sequence homology in T. gondii RH","pmids":["17626366"],"confidence":"Low","gaps":["Class-level inference only, no direct HDAC3 target validation","Distinguishes Class I from Class III but not individual HDAC enzymes","No mechanistic link to gene regulation"],"attribution":[{"species":"Toxoplasma gondii","strain":"RH"}]},{"year":2009,"claim":"Identifying TgHDAC3 as the direct target of FR235222 and pinpointing the T99 catalytic residue answered which specific enzyme mediates HDAC inhibitor activity and revealed an Apicomplexa-specific determinant enabling parasite-selective targeting.","evidence":"Drug target identification with active-site mutagenesis of TgHDAC3 T99 and phenotypic rescue in T. gondii","pmids":["19349466"],"confidence":"High","gaps":["Structural basis of T99 selectivity not resolved at atomic level","Direct substrate spectrum of HDAC3 not defined"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2009,"claim":"Linking HDAC3 inhibition to genome-wide transcriptional de-repression and tachyzoite-to-bradyzoite conversion established HDAC3 as a central regulator of stage-specific gene expression rather than merely a growth factor.","evidence":"FR235222 treatment with transcriptome analysis and stage conversion assays in T. gondii","pmids":["19349466"],"confidence":"High","gaps":["Recruitment mechanism to specific promoters unknown at this stage","Direct versus indirect targets among the ~370 genes not distinguished"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2010,"claim":"Confirming HDAC3 as the pharmacological target across tachyzoite and bradyzoite/cyst stages and using its structure for rational drug design demonstrated the enzyme's relevance to both acute and chronic infection.","evidence":"Ex vivo cyst treatment, fluorescent labeling, structure-guided medicinal chemistry, and in vivo mouse cyst infection assays","pmids":["20713670"],"confidence":"Medium","gaps":["No high-resolution experimental structure reported","Selectivity over host HDAC3 characterized only pharmacologically"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2020,"claim":"Discovering that MORC in complex with AP2 factors recruits HDAC3 to sexual-stage promoters resolved how HDAC3 achieves locus specificity, defining it as the enzymatic effector of a sequence-directed repressor complex.","evidence":"Reciprocal Co-IP, chromatin accessibility assays, conditional MORC depletion, and transcriptome analysis in T. gondii","pmids":["32094587"],"confidence":"High","gaps":["Which AP2 factors direct which loci not fully enumerated","Order of assembly and role of HDAC3 catalytic activity within the complex not dissected"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"claim":"Identifying specific ApiAP2 heterodimers (AP2XII-1/AP2XI-2) and additional factors (AP2XII-2) that target the MORC-HDAC3 complex to merozoite and sexual-stage loci established a combinatorial code assigning the repressor complex to distinct developmental gene sets.","evidence":"Conditional depletion, ChIP/CUT&Tag, ATAC-seq, Co-IP, and transcriptome analysis in T. gondii (with corroborating preprint)","pmids":["38093015","36786611","36711883"],"confidence":"High","gaps":["Combinatorial rules governing AP2 factor pairing incompletely mapped","Contribution of HDAC3 deacetylase activity versus complex scaffolding not separated"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"claim":"Extending the complex to AP2XII-5 (with the novel AIP1) and demonstrating a hierarchical AP2XII-1-led cascade upstream of HDAC3 clarified that multiple ApiAP2 modules feed into a shared MORC-HDAC3 repressive hub.","evidence":"Co-IP/mass spectrometry complex identification, conditional depletion/knockout, and transcriptome/chromatin binding assays in T. gondii","pmids":["39716984","38791568"],"confidence":"Medium","gaps":["Functional role of AIP1 within the complex undefined","Single-lab complex compositions await independent replication"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"claim":"Showing apicidin inhibition of HDAC3 de-represses sporozoite-specific genes broadened HDAC3's repressive scope to oocyst/sporozoite programs, reinforcing its role as a global gatekeeper of non-tachyzoite gene expression.","evidence":"Apicidin inhibition with immunofluorescence, immunoprecipitation, and mass spectrometry in T. gondii","pmids":["39802703"],"confidence":"Medium","gaps":["Apicidin selectivity for HDAC3 over other HDACs not fully controlled","Direct promoter occupancy at sporozoite genes not shown"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2025,"claim":"Placing the MORC/HDAC3 complex epistatically upstream of BFD1 and identifying AP2X-1 as a further modulator situated HDAC3 within the master bradyzoite differentiation pathway controlling chronic persistence.","evidence":"Genetic epistasis analysis, Co-IP, CUT&Tag, ATAC-seq, conditional knockout, single-cell and bulk transcriptomics in T. gondii","pmids":["40389644","40823841"],"confidence":"Medium","gaps":["Molecular mechanism by which HDAC3/MORC represses BFD1 not defined","Whether the epistatic relationship is direct or indirect unresolved"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":null,"claim":"The direct non-histone and histone substrate spectrum of TgHDAC3 and the precise contribution of its catalytic deacetylation versus its scaffolding within the MORC complex to repression remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined catalog of endogenous acetyl-substrates","Catalytic-dead separation-of-function experiments not reported","No high-resolution structure of the complete MORC-HDAC3-AP2 assembly"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["MORC-HDAC3-AP2 transcriptional repressor complex","AP2XII-5-MORC-HDAC3-AIP1 nuclear repressor complex"],"partners":["MORC","AP2XII-1","AP2XI-2","AP2XII-2","AP2XII-5","AP2X-1","AIP1","BFD1 (EPISTATIC DOWNSTREAM REGULATOR)"],"other_free_text":["Catalytic activity depends on the Apicomplexa-specific active-site residue T99, which is also the determinant of FR235222 sensitivity [#0].","Directly targeted by the HDAC inhibitors FR235222 and apicidin; class I HDAC inhibitors (SAHA, scriptaid, TSA) inhibit tachyzoite proliferation [#0, #11, #12].","Recruited to promoters by sequence-specific ApiAP2 transcription factors in a hierarchical cascade to repress bradyzoite, merozoite, sexual-stage, and sporozoite gene programs [#4, #7, #9, #11]."]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"19349466","id":"PMC_19349466","title":"Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites.","date":"2009","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19349466","citation_count":146,"is_preprint":false},{"pmid":"32094587","id":"PMC_32094587","title":"A MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitment.","date":"2020","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32094587","citation_count":102,"is_preprint":false},{"pmid":"38093015","id":"PMC_38093015","title":"In vitro production of cat-restricted Toxoplasma pre-sexual stages.","date":"2023","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/38093015","citation_count":52,"is_preprint":false},{"pmid":"17626366","id":"PMC_17626366","title":"Scriptaid and suberoylanilide hydroxamic acid are histone deacetylase inhibitors with potent anti-Toxoplasma gondii activity in vitro.","date":"2007","source":"The Journal of parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/17626366","citation_count":52,"is_preprint":false},{"pmid":"20713670","id":"PMC_20713670","title":"Activity of the histone deacetylase inhibitor FR235222 on Toxoplasma gondii: inhibition of stage conversion of the parasite cyst form and study of new derivative compounds.","date":"2010","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/20713670","citation_count":51,"is_preprint":false},{"pmid":"36786611","id":"PMC_36786611","title":"Toxoplasma gondii AP2XII-2 Contributes to Transcriptional Repression for Sexual Commitment.","date":"2023","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/36786611","citation_count":32,"is_preprint":false},{"pmid":"33360687","id":"PMC_33360687","title":"HDAC inhibitors Tubastatin A and SAHA affect parasite cell division and are potential anti-Toxoplasma gondii chemotherapeutics.","date":"2020","source":"International journal for parasitology. Drugs and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/33360687","citation_count":28,"is_preprint":false},{"pmid":"38791568","id":"PMC_38791568","title":"AP2XII-1 and AP2XI-2 Suppress Schizogony Gene Expression in Toxoplasma gondii.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38791568","citation_count":12,"is_preprint":false},{"pmid":"39716984","id":"PMC_39716984","title":"A Novel Nuclear Protein Complex Controlling the Expression of Developmentally Regulated Genes in Toxoplasma Gondii.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39716984","citation_count":5,"is_preprint":false},{"pmid":"36711883","id":"PMC_36711883","title":"In vitro production of cat-restricted Toxoplasma pre-sexual stages by epigenetic reprogramming.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36711883","citation_count":5,"is_preprint":false},{"pmid":"40389644","id":"PMC_40389644","title":"Uncovering biomarkers for chronic toxoplasmosis detection highlights alternative pathways shaping parasite dormancy.","date":"2025","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40389644","citation_count":3,"is_preprint":false},{"pmid":"39802703","id":"PMC_39802703","title":"Proteomic identification of a Toxoplasma gondii sporozoite-specific antigen using HDAC3 inhibitor-treated tachyzoites as surrogate.","date":"2024","source":"FEMS microbes","url":"https://pubmed.ncbi.nlm.nih.gov/39802703","citation_count":2,"is_preprint":false},{"pmid":"40886497","id":"PMC_40886497","title":"Decoding the epigenetic blueprint behind Toxoplasma (pre)sexual commitment and chronic persistence.","date":"2025","source":"Current opinion in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40886497","citation_count":1,"is_preprint":false},{"pmid":"40823841","id":"PMC_40823841","title":"AP2X-1 is a negative regulator of Toxoplasma gondii sexual commitment.","date":"2025","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/40823841","citation_count":1,"is_preprint":false},{"pmid":"40741955","id":"PMC_40741955","title":"In vitro and in vivo activity of quisinostat against Toxoplasma gondii.","date":"2025","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/40741955","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10167,"output_tokens":3693,"usd":0.042948,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9921,"output_tokens":4439,"usd":0.08029,"stage2_stop_reason":"end_turn"},"total_usd":0.123238,"stage1_batch_id":"msgbatch_01WokvBYTB6JLnYrpD4rXnyV","stage2_batch_id":"msgbatch_01M7hsQDvz6AqVC9DLVjQzzc","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"TgHDAC3 was identified as the direct molecular target of the cyclic tetrapeptide HDACi FR235222 in Toxoplasma tachyzoites; the conserved Apicomplexa-specific residue T99 in TgHDAC3 is critical for the drug's inhibitory activity, established by active-site mutagenesis showing that mutation of T99 abolishes FR235222 inhibition.\",\n      \"method\": \"Drug target identification via genetic/biochemical approach; active-site mutagenesis of TgHDAC3 T99; phenotypic rescue\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis identifying a specific catalytic residue required for inhibitor activity, single lab but multiple functional validations\",\n      \"pmids\": [\"19349466\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Inhibition of TgHDAC3 by FR235222 induces differentiation of tachyzoites (replicative stage) into bradyzoites (non-replicative stage) and influences the expression of approximately 370 genes, a third of which are stage-specifically expressed, establishing TgHDAC3 as a central regulator of gene expression and stage conversion.\",\n      \"method\": \"HDACi treatment (FR235222) followed by transcriptome analysis and stage conversion assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with specific target validation plus genome-wide transcriptome analysis, single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"19349466\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FR235222 targets TgHDAC3 in bradyzoites and cyst forms in vitro and ex vivo; structural knowledge of TgHDAC3 was used to rationally design new FR235222 derivative compounds with improved selectivity, confirming HDAC3 as the pharmacological target in both tachyzoite and bradyzoite stages.\",\n      \"method\": \"Ex vivo cyst treatment, fluorescent labeling, structure-guided medicinal chemistry, in vivo cyst infection assay in mice\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-guided drug design using TgHDAC3 as target, confirmed by ex vivo and in vivo efficacy, single lab\",\n      \"pmids\": [\"20713670\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HDAC3 is recruited to chromatin at sexual-stage gene promoters by the MORC protein in complex with AP2 transcription factors, thereby restricting chromatin accessibility and repressing genes exclusively expressed during sexual stages; this positions HDAC3 as an effector within a MORC-AP2 transcriptional repressor complex.\",\n      \"method\": \"Co-immunoprecipitation, chromatin accessibility assays, conditional depletion of MORC, transcriptome analysis\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing the MORC-AP2-HDAC3 complex, conditional depletion with defined transcriptional phenotype, chromatin accessibility assays, replicated in subsequent studies\",\n      \"pmids\": [\"32094587\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AP2XII-1 and AP2XI-2 bind DNA as heterodimers at merozoite gene promoters in tachyzoites and recruit MORC and HDAC3, thereby limiting chromatin accessibility and repressing merozoite-specific transcription; depletion of both factors causes epigenetic rewiring and tachyzoite-to-merozoite transition.\",\n      \"method\": \"Conditional depletion, ChIP/CUT&Tag, chromatin accessibility (ATAC-seq), Co-immunoprecipitation, transcriptome analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, CUT&Tag, ATAC-seq, and conditional KO with defined stage-transition phenotype, replicated across peer-reviewed paper and preprint\",\n      \"pmids\": [\"38093015\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AP2XII-2 co-occupies genomic loci associated with sexually committed parasites together with HDAC3 and MORC, contributing to the repression of a subset of sexual-stage genes including AP2X-10 and AAH1, as demonstrated by CUT&Tag chromatin profiling and conditional depletion.\",\n      \"method\": \"CUT&Tag, conditional depletion, transcriptome analysis\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag and conditional KO showing co-occupancy and gene de-repression, single lab\",\n      \"pmids\": [\"36786611\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AP2XII-5 forms a nuclear complex with MORC and HDAC3 (as well as the novel protein AIP1) that suppresses developmentally regulated genes at tachyzoite stage; AP2XII-5 binds promoters of developmentally activated genes and recruits MORC and HDAC3 to repress their expression.\",\n      \"method\": \"Immunoprecipitation and mass spectrometry (complex identification), conditional depletion, transcriptome and chromatin binding assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identifying the complex, conditional depletion with defined transcriptional phenotype, single lab\",\n      \"pmids\": [\"39716984\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AP2XII-1 and AP2XI-2 target the MORC-HDAC3 complex to merozoite gene promoters; their disruption profoundly alters expression of merozoite-specific genes, with AP2XII-1 specifically binding a subset of ApiAP2 transcription factors including AP2XI-2, establishing a hierarchical ApiAP2 regulatory cascade upstream of HDAC3-mediated repression.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, conditional knockout, transcriptome analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS for complex identification, conditional KO with transcriptional phenotype, single lab\",\n      \"pmids\": [\"38791568\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MORC and HDAC3 epistatically regulate BFD1 (a key bradyzoite regulator), placing the MORC/HDAC3 repressor complex upstream of BFD1 in the pathway controlling bradyzoite gene expression and chronic persistence.\",\n      \"method\": \"Genetic epistasis analysis, conditional depletion, transcriptome analysis\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by conditional depletions with transcriptional readouts, single lab\",\n      \"pmids\": [\"40389644\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AP2X-1 associates with the HDAC3/MORC complex and co-occupies promoters of bradyzoite- and sexual stage-specific genes; loss of AP2X-1 leads to upregulation of these genes, chromatin decompaction at target loci, and induction of bradyzoite differentiation and sexual commitment, indicating AP2X-1 modulates HDAC3/MORC function to repress developmental gene expression.\",\n      \"method\": \"Co-immunoprecipitation (complex association), CUT&Tag chromatin profiling, ATAC-seq, conditional knockout, transcriptome analysis, single-cell sequencing\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, CUT&Tag, ATAC-seq, and conditional KO with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"40823841\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In tachyzoites, AP2XII-1 and AP2XI-2 bind merozoite gene promoters as heterodimers and recruit MORC and HDAC3 to restrict chromatin accessibility; this was confirmed independently in a preprint preceding the published Nature paper.\",\n      \"method\": \"Conditional depletion, CUT&Tag, ATAC-seq, Co-immunoprecipitation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint with multiple orthogonal methods, subsequently confirmed in the peer-reviewed publication (PMID 38093015)\",\n      \"pmids\": [\"36711883\"],\n      \"is_preprint\": true,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Pharmacological inhibition of HDAC3 with apicidin (a commercially available HDACi) in tachyzoites induces expression of sporozoite-specific genes including SporoSAG and LEA860, confirming HDAC3 actively represses oocyst/sporozoite-stage gene expression in tachyzoites.\",\n      \"method\": \"Drug inhibition (apicidin), immunofluorescence microscopy, immunoprecipitation, mass spectrometry\",\n      \"journal\": \"FEMS microbes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition of HDAC3 with stage-specific transcriptional and proteomic readouts, single lab\",\n      \"pmids\": [\"39802703\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"T. gondii expresses a Class I HDAC enzyme homologous to human HDAC3; hydroxamic acid HDACi compounds (SAHA, scriptaid, TSA) at nanomolar concentrations inhibit tachyzoite proliferation, while the Class III HDAC inhibitor nicotinamide had minimal anti-parasitic activity, functionally implicating Class I HDAC (HDAC3) in tachyzoite replication.\",\n      \"method\": \"In vitro anti-parasitic proliferation assay with selective HDAC inhibitors; sequence homology\",\n      \"journal\": \"The Journal of parasitology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological profiling without direct target validation, class-level inference only\",\n      \"pmids\": [\"17626366\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"RH\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Treatment with the HDAC inhibitor Tubastatin A (TST) led to increased histone H4 acetylation and decreased H3 acetylation, impaired endodyogeny (budding of daughter cells), caused centrosome dispersal, apicoplast division defects, mitochondrial membrane potential disruption, and IMC assembly failure; TST possibly inhibits HDAC3 and other HDACs involved in non-histone protein modification.\",\n      \"method\": \"Western blotting (histone acetylation), fluorescence and electron microscopy, mitochondrial membrane potential assay, in vitro proliferation assay\",\n      \"journal\": \"International journal for parasitology. Drugs and drug resistance\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibition without direct TgHDAC3 target confirmation; multiple HDACs potentially involved\",\n      \"pmids\": [\"33360687\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"RH; ME49\"}]\n    }\n  ],\n  \"current_model\": \"TgHDAC3 is a histone deacetylase whose catalytic activity (requiring the conserved T99 residue) maintains transcriptional repression of developmental-stage-specific genes by being recruited, as part of a MORC/AP2 transcription factor repressor complex, to the promoters of bradyzoite, merozoite, and sexual-stage genes in proliferating tachyzoites; inhibition or disruption of this complex de-represses these stage-specific gene programs, triggering irreversible stage conversion, and HDAC3 additionally functions epistatically upstream of the master bradyzoite regulator BFD1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TgHDAC3 is a class I histone deacetylase in Toxoplasma gondii that acts as the central epigenetic enforcer of developmental-stage identity, maintaining transcriptional repression of stage-specific gene programs in proliferating tachyzoites [#1]. It is the direct molecular target of the cyclic tetrapeptide inhibitor FR235222, and the Apicomplexa-specific active-site residue T99 is required for this inhibition, defining a druggable catalytic pocket distinct from host HDACs [#0]. Pharmacological inhibition of TgHDAC3 de-represses roughly 370 genes—a third of them stage-specific—and drives conversion of replicative tachyzoites into non-replicative bradyzoites [#1], and independently induces sporozoite-stage genes such as SporoSAG and LEA860 [#11]. Mechanistically, HDAC3 does not act autonomously but is recruited to promoters of bradyzoite, merozoite, and sexual-stage genes as the effector of a MORC-scaffolded repressor complex, where sequence-specific ApiAP2 transcription factors—including AP2XII-1/AP2XI-2 heterodimers at merozoite loci, AP2XII-2, AP2XII-5, and AP2X-1—target the MORC-HDAC3 module to particular loci to restrict chromatin accessibility [#3, #4, #6, #9]. This forms a hierarchical ApiAP2 cascade upstream of HDAC3-mediated deacetylation [#7], and the MORC/HDAC3 complex acts epistatically upstream of the master bradyzoite regulator BFD1 to control chronic-stage differentiation [#8]. Disruption of this complex causes chromatin decompaction at target loci and irreversible stage conversion, making the pathway both a driver of parasite persistence and an antiparasitic drug target [#4, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that a Class I HDAC contributes to tachyzoite proliferation was the first step toward identifying a druggable chromatin regulator, addressing whether HDAC activity is required for parasite growth.\",\n      \"evidence\": \"In vitro anti-parasitic proliferation assays with class-selective HDAC inhibitors and sequence homology in T. gondii RH\",\n      \"pmids\": [\"17626366\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Class-level inference only, no direct HDAC3 target validation\", \"Distinguishes Class I from Class III but not individual HDAC enzymes\", \"No mechanistic link to gene regulation\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"RH\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying TgHDAC3 as the direct target of FR235222 and pinpointing the T99 catalytic residue answered which specific enzyme mediates HDAC inhibitor activity and revealed an Apicomplexa-specific determinant enabling parasite-selective targeting.\",\n      \"evidence\": \"Drug target identification with active-site mutagenesis of TgHDAC3 T99 and phenotypic rescue in T. gondii\",\n      \"pmids\": [\"19349466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of T99 selectivity not resolved at atomic level\", \"Direct substrate spectrum of HDAC3 not defined\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linking HDAC3 inhibition to genome-wide transcriptional de-repression and tachyzoite-to-bradyzoite conversion established HDAC3 as a central regulator of stage-specific gene expression rather than merely a growth factor.\",\n      \"evidence\": \"FR235222 treatment with transcriptome analysis and stage conversion assays in T. gondii\",\n      \"pmids\": [\"19349466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment mechanism to specific promoters unknown at this stage\", \"Direct versus indirect targets among the ~370 genes not distinguished\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Confirming HDAC3 as the pharmacological target across tachyzoite and bradyzoite/cyst stages and using its structure for rational drug design demonstrated the enzyme's relevance to both acute and chronic infection.\",\n      \"evidence\": \"Ex vivo cyst treatment, fluorescent labeling, structure-guided medicinal chemistry, and in vivo mouse cyst infection assays\",\n      \"pmids\": [\"20713670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution experimental structure reported\", \"Selectivity over host HDAC3 characterized only pharmacologically\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovering that MORC in complex with AP2 factors recruits HDAC3 to sexual-stage promoters resolved how HDAC3 achieves locus specificity, defining it as the enzymatic effector of a sequence-directed repressor complex.\",\n      \"evidence\": \"Reciprocal Co-IP, chromatin accessibility assays, conditional MORC depletion, and transcriptome analysis in T. gondii\",\n      \"pmids\": [\"32094587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which AP2 factors direct which loci not fully enumerated\", \"Order of assembly and role of HDAC3 catalytic activity within the complex not dissected\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying specific ApiAP2 heterodimers (AP2XII-1/AP2XI-2) and additional factors (AP2XII-2) that target the MORC-HDAC3 complex to merozoite and sexual-stage loci established a combinatorial code assigning the repressor complex to distinct developmental gene sets.\",\n      \"evidence\": \"Conditional depletion, ChIP/CUT&Tag, ATAC-seq, Co-IP, and transcriptome analysis in T. gondii (with corroborating preprint)\",\n      \"pmids\": [\"38093015\", \"36786611\", \"36711883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial rules governing AP2 factor pairing incompletely mapped\", \"Contribution of HDAC3 deacetylase activity versus complex scaffolding not separated\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extending the complex to AP2XII-5 (with the novel AIP1) and demonstrating a hierarchical AP2XII-1-led cascade upstream of HDAC3 clarified that multiple ApiAP2 modules feed into a shared MORC-HDAC3 repressive hub.\",\n      \"evidence\": \"Co-IP/mass spectrometry complex identification, conditional depletion/knockout, and transcriptome/chromatin binding assays in T. gondii\",\n      \"pmids\": [\"39716984\", \"38791568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of AIP1 within the complex undefined\", \"Single-lab complex compositions await independent replication\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing apicidin inhibition of HDAC3 de-represses sporozoite-specific genes broadened HDAC3's repressive scope to oocyst/sporozoite programs, reinforcing its role as a global gatekeeper of non-tachyzoite gene expression.\",\n      \"evidence\": \"Apicidin inhibition with immunofluorescence, immunoprecipitation, and mass spectrometry in T. gondii\",\n      \"pmids\": [\"39802703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apicidin selectivity for HDAC3 over other HDACs not fully controlled\", \"Direct promoter occupancy at sporozoite genes not shown\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placing the MORC/HDAC3 complex epistatically upstream of BFD1 and identifying AP2X-1 as a further modulator situated HDAC3 within the master bradyzoite differentiation pathway controlling chronic persistence.\",\n      \"evidence\": \"Genetic epistasis analysis, Co-IP, CUT&Tag, ATAC-seq, conditional knockout, single-cell and bulk transcriptomics in T. gondii\",\n      \"pmids\": [\"40389644\", \"40823841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which HDAC3/MORC represses BFD1 not defined\", \"Whether the epistatic relationship is direct or indirect unresolved\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct non-histone and histone substrate spectrum of TgHDAC3 and the precise contribution of its catalytic deacetylation versus its scaffolding within the MORC complex to repression remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined catalog of endogenous acetyl-substrates\", \"Catalytic-dead separation-of-function experiments not reported\", \"No high-resolution structure of the complete MORC-HDAC3-AP2 assembly\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004407\", \"supporting_discovery_ids\": [0, 1, 12], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0003714\", \"supporting_discovery_ids\": [3, 4, 6, 9], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000785\", \"supporting_discovery_ids\": [3, 4, 9], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0045892\", \"supporting_discovery_ids\": [3, 4, 6, 9, 11], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0030154\", \"supporting_discovery_ids\": [1, 4, 8, 9], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0006338\", \"supporting_discovery_ids\": [3, 4, 9], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [\n      \"MORC-HDAC3-AP2 transcriptional repressor complex\",\n      \"AP2XII-5-MORC-HDAC3-AIP1 nuclear repressor complex\"\n    ],\n    \"partners\": [\n      \"MORC\",\n      \"AP2XII-1\",\n      \"AP2XI-2\",\n      \"AP2XII-2\",\n      \"AP2XII-5\",\n      \"AP2X-1\",\n      \"AIP1\",\n      \"BFD1 (epistatic downstream regulator)\"\n    ],\n    \"other_free_text\": [\n      \"Catalytic activity depends on the Apicomplexa-specific active-site residue T99, which is also the determinant of FR235222 sensitivity [#0].\",\n      \"Directly targeted by the HDAC inhibitors FR235222 and apicidin; class I HDAC inhibitors (SAHA, scriptaid, TSA) inhibit tachyzoite proliferation [#0, #11, #12].\",\n      \"Recruited to promoters by sequence-specific ApiAP2 transcription factors in a hierarchical cascade to repress bradyzoite, merozoite, sexual-stage, and sporozoite gene programs [#4, #7, #9, #11].\"\n    ]\n  },\n  \"strain_conflicts\": []\n}\n```","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_227290","name":"HDAC3","product":"histone deacetylase HDAC3","uniprot_acc":"A0A125YPH4","chromosome":"TGME49_chrX","start_pos":1041747},{"strain":"GT1","gene_id":"TGGT1_227290","name":null,"product":"histone deacetylase HDAC3","uniprot_acc":null,"chromosome":"TGGT1_chrX","start_pos":951051},{"strain":"RH88","gene_id":"TGRH88_046800","name":null,"product":"histone deacetylase HDAC3","uniprot_acc":null,"chromosome":"CM023091","start_pos":6526581},{"strain":"VEG","gene_id":"TGVEG_227290","name":null,"product":"histone deacetylase HDAC3","uniprot_acc":"A0A0F7V6N9","chromosome":"TGVEG_chrX","start_pos":934218}]}