{"gene":"PF3D7_1115200","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2016,"finding":"SET7 (PF3D7_1115200) is an AdoMet-dependent histone H3 lysine methyltransferase with highest activity towards lysines K4 and K9, and to a lesser extent K36, as demonstrated by in vitro enzymatic characterization of recombinant protein expressed and purified in sufficient quantities for full steady-state kinetic analysis.","method":"In vitro enzymatic assay with recombinant purified protein; steady-state kinetics","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — full in vitro enzymatic reconstitution with recombinant protein, steady-state kinetics, multiple substrate specificities tested; single lab but multiple orthogonal methods","pmids":["26902486"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"SET7 displays specific protein substrate preference towards nucleosomes with pre-existing histone H3 lysine 14 acetylation (H3K14ac), establishing a functional crosstalk between H3K14ac and SET7-mediated H3K4/K9 methylation.","method":"In vitro enzymatic assay with recombinant protein using nucleosome substrates bearing defined pre-existing modifications","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined nucleosome substrates, single lab, directly demonstrated substrate preference","pmids":["26902486"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"SET7 localizes to distinct cytoplasmic foci adjacent to the nucleus in erythrocytic stage and liver stage parasites, and is distributed throughout the cytoplasm in salivary gland sporozoites, as determined by direct cellular imaging.","method":"Cellular localization by fluorescence imaging across multiple parasite life cycle stages","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment, multiple life cycle stages examined, single lab, no functional consequence directly linked to localization","pmids":["26902486"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"finding":"Prokaryotic expression of the putative active domain of SET7 did not yield detectable HKMT activity towards recombinant P. falciparum histones (negative result); however, expression in a eukaryotic in vitro system showed HKMT activity towards H3.","method":"Prokaryotic and eukaryotic in vitro expression systems; HKMT activity assay with recombinant histones","journal":"International journal for parasitology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro activity assay, single lab, limited detail on which specific SET protein gave H3 activity; abstract is broad across multiple SET proteins","pmids":["18299133"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"SET7 was identified as a proximity interactor of PfSAMS (S-adenosylmethionine synthetase), the enzyme that synthesizes the methyl donor SAM, by proximity-dependent biotin identification (BioID) proteomics, placing SET7 within the SAM-dependent methylation network in blood-stage parasites.","method":"Proximity-dependent biotin identification (BioID) / proximity ligation proteomics","journal":"Microorganisms","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single proximity-ligation proteomics screen, no reciprocal validation, single lab; SET7 is one of 1114 identified interactors","pmids":["35889137"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"SET7 transcript is destabilized in the absence of the translational repressors DOZI and CITH in gametocytes, indicating that SET7 mRNA is subject to translational repression in gametocytes and may have a role in epigenetic control of the ookinete.","method":"Transcriptome analysis (suppression subtractive hybridization and RT-PCR) comparing wild-type and DOZI/CITH knockout gametocytes","journal":"BMC genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect evidence from transcript-level analysis in DOZI/CITH knockouts, no direct functional validation of SET7 translational repression, single method","pmids":["23586929"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"SET7 (PF3D7_1115200) is a cytoplasmic, AdoMet-dependent histone H3 lysine methyltransferase that methylates H3K4 and H3K9 (and to a lesser extent H3K36) preferentially on nucleosomes bearing pre-existing H3K14 acetylation; it localizes to distinct cytoplasmic foci adjacent to the nucleus in erythrocytic and liver stage parasites and throughout the cytoplasm in salivary gland sporozoites, and its mRNA is subject to translational repression by DOZI/CITH in gametocytes."},"narrative":{"mechanistic_narrative":"SET7 (PF3D7_1115200) is an AdoMet-dependent histone H3 lysine methyltransferase of Plasmodium falciparum that methylates H3K4 and H3K9, and to a lesser extent H3K36, as established by steady-state kinetic analysis of recombinant enzyme [PMID:26902486]. Its activity is context-dependent: SET7 preferentially methylates nucleosomes carrying pre-existing H3K14 acetylation, defining a histone crosstalk in which H3K14ac primes SET7-mediated H3K4/K9 methylation [PMID:26902486]. Consistent with dependence on the methyl donor SAM, SET7 was recovered as a proximity interactor of the S-adenosylmethionine synthetase PfSAMS, placing it within the parasite's SAM-dependent methylation network [PMID:35889137]. SET7 localizes not to the nucleus but to distinct cytoplasmic foci adjacent to the nucleus in erythrocytic and liver stages, and throughout the cytoplasm in salivary gland sporozoites [PMID:26902486], and its transcript is destabilized in the absence of the translational repressors DOZI and CITH in gametocytes, indicating stage-specific translational control [PMID:23586929]. Beyond these enzymatic, localization, and regulatory observations, the in vivo chromatin targets and functional consequences of SET7 activity have not been characterized in the available corpus.","teleology":[{"year":2008,"claim":"The question of whether SET7 is catalytically active as a histone methyltransferase was first addressed by testing recombinant expression systems, showing that folding context matters for its activity.","evidence":"Prokaryotic vs eukaryotic in vitro expression of the putative active domain and HKMT assay against recombinant histones","pmids":["18299133"],"confidence":"Medium","gaps":["Abstract is broad across multiple SET proteins; specific attribution of H3 activity to SET7 is limited","No lysine-residue specificity established at this stage","No cellular or in vivo confirmation of activity"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"Full biochemical reconstitution established SET7 as a bona fide AdoMet-dependent H3 methyltransferase and defined its residue specificity, resolving what earlier expression tests left ambiguous.","evidence":"In vitro steady-state kinetics with recombinant purified enzyme testing multiple lysine substrates","pmids":["26902486"],"confidence":"High","gaps":["In vivo H3K4/K9/K36 targets and genomic distribution not mapped","Physiological relevance of the minor H3K36 activity unclear"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"By using nucleosomes bearing defined pre-existing modifications, the study showed SET7 is regulated by histone crosstalk, requiring H3K14 acetylation to efficiently methylate its targets.","evidence":"In vitro assay with recombinant SET7 on modified nucleosome substrates","pmids":["26902486"],"confidence":"High","gaps":["The writer enzyme(s) generating H3K14ac in vivo not identified in this corpus","Whether the crosstalk operates on chromatin in living parasites untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"Cellular imaging addressed where SET7 acts, unexpectedly placing a histone methyltransferase in cytoplasmic foci rather than the nucleus and revealing stage-dependent redistribution.","evidence":"Fluorescence imaging across erythrocytic, liver, and sporozoite stages","pmids":["26902486"],"confidence":"Medium","gaps":["How a cytoplasmic enzyme accesses chromatin substrates is unresolved","No functional consequence linked to the localization pattern"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"Transcriptome analysis of DOZI/CITH knockout gametocytes placed SET7 under post-transcriptional control, implicating it in stage-specific epigenetic regulation during transmission.","evidence":"Suppression subtractive hybridization and RT-PCR comparing wild-type and DOZI/CITH knockout gametocytes","pmids":["23586929"],"confidence":"Low","gaps":["Indirect transcript-level evidence; SET7 translational repression not directly demonstrated","No functional test of a SET7 role in the ookinete"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Proximity proteomics connected SET7 to the SAM-synthesizing enzyme PfSAMS, providing a spatial link to the methyl-donor supply consistent with its AdoMet dependence.","evidence":"BioID proximity-dependent biotin identification in blood-stage parasites","pmids":["35889137"],"confidence":"Low","gaps":["Single proximity screen without reciprocal validation; SET7 is one of >1000 hits","Direct or functional interaction with PfSAMS not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The in vivo genomic targets, chromatin context, and biological function of SET7-mediated methylation across the parasite life cycle remain to be defined.","evidence":"No direct in vivo functional or genome-wide localization study of SET7 in the corpus","pmids":[],"confidence":"Low","gaps":["No loss-of-function phenotype for SET7 reported","No genome-wide mapping of SET7-dependent H3K4/K9 marks","Mechanism reconciling cytoplasmic localization with histone substrates unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFSAMS (S-ADENOSYLMETHIONINE SYNTHETASE) — PROXIMITY INTERACTOR BY BIOID [#4]"],"other_free_text":["AdoMet(SAM)-dependent enzyme; methylates H3K4 and H3K9 with lesser activity toward H3K36 [#0]","Prefers nucleosomes with pre-existing H3K14 acetylation, defining H3K14ac–H3K4/K9 crosstalk [#1]","Activity depends on eukaryotic expression context; prokaryotically expressed domain was inactive [#3]","Localizes to cytoplasmic foci adjacent to the nucleus (erythrocytic, liver stages) and throughout the cytoplasm in salivary gland sporozoites [#2]","SET7 transcript destabilized in DOZI/CITH knockout gametocytes, implying translational repression during transmission stages [#5]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"18299133","id":"PMC_18299133","title":"Histone lysine methyltransferases and demethylases in Plasmodium falciparum.","date":"2008","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/18299133","citation_count":106,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"26902486","id":"PMC_26902486","title":"Plasmodium falciparum PfSET7: enzymatic characterization and cellular localization of a novel protein methyltransferase in sporozoite, liver and erythrocytic stage parasites.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26902486","citation_count":34,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfSET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41417877","id":"","title":"Histone lactylation: A new epigenetic mark in the malaria parasite Plasmodium.","date":"2025","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41417877","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41220000","id":"","title":"Influence of biophysical and biochemical cues on Plasmodium sporozoite dynamics in skin tissue.","date":"2025","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/41220000","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38892332","id":"","title":"Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38892332","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35889137","id":"","title":"Plasmodium falciparum S-Adenosylmethionine Synthetase Is Essential for Parasite Survival through a Complex Interaction Network with Cytoplasmic and Nuclear Proteins.","date":"2022","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/35889137","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35433676","id":"","title":"Histone Modification Landscapes as a Roadmap for Malaria Parasite Development.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35433676","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"36451097","id":"","title":"A manually curated annotation characterises genomic features of P. falciparum lncRNAs.","date":"2022","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36451097","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33585284","id":"","title":"Preparing for Transmission: Gene Regulation in Plasmodium Sporozoites.","date":"2021","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33585284","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35051657","id":"","title":"A Dynamic and Combinatorial Histone Code Drives Malaria Parasite Asexual and Sexual Development.","date":"2022","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/35051657","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37013531","id":"","title":"Plasmodium falciparum gametocytes display global chromatin remodelling during sexual differentiation.","date":"2023","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/37013531","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37232495","id":"","title":"Chemo-proteomics in antimalarial target identification and engagement.","date":"2023","source":"Medicinal research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/37232495","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35464842","id":"","title":"Identification of Co-Existing Mutations and Gene Expression Trends Associated With K13-Mediated Artemisinin Resistance in Plasmodium falciparum.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35464842","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33431834","id":"","title":"Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33431834","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29529020","id":"","title":"The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen-encoding var genes.","date":"2018","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/29529020","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31615031","id":"","title":"The G9a Histone Methyltransferase Inhibitor BIX-01294 Modulates Gene Expression during Plasmodium falciparum Gametocyte Development and Transmission.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31615031","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29308121","id":"","title":"Histone lysine methyltransferase structure activity relationships that allow for segregation of G9a inhibition and anti-Plasmodium activity.","date":"2017","source":"MedChemComm","url":"https://pubmed.ncbi.nlm.nih.gov/29308121","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28377601","id":"","title":"Quantitative chromatin proteomics reveals a dynamic histone post-translational modification landscape that defines asexual and sexual Plasmodium falciparum parasites.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28377601","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23586929","id":"","title":"Changes in the transcriptome of the malaria parasite Plasmodium falciparum during the initial phase of transmission from the human to the mosquito.","date":"2013","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/23586929","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SET7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21305,"output_tokens":1582,"usd":0.043823,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6640,"output_tokens":2929,"usd":0.053213,"stage2_stop_reason":"end_turn"},"total_usd":0.097036,"stage1_batch_id":"msgbatch_01SRp5hyRc82zNjddxyCCXGk","stage2_batch_id":"msgbatch_01K3BTmBazRo3pRrMvyaPMTY","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"SET7 (PF3D7_1115200) is an AdoMet-dependent histone H3 lysine methyltransferase with highest activity towards lysines K4 and K9, and to a lesser extent K36, as demonstrated by in vitro enzymatic characterization of recombinant protein expressed and purified in sufficient quantities for full steady-state kinetic analysis.\",\n      \"method\": \"In vitro enzymatic assay with recombinant purified protein; steady-state kinetics\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — full in vitro enzymatic reconstitution with recombinant protein, steady-state kinetics, multiple substrate specificities tested; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26902486\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SET7 displays specific protein substrate preference towards nucleosomes with pre-existing histone H3 lysine 14 acetylation (H3K14ac), establishing a functional crosstalk between H3K14ac and SET7-mediated H3K4/K9 methylation.\",\n      \"method\": \"In vitro enzymatic assay with recombinant protein using nucleosome substrates bearing defined pre-existing modifications\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined nucleosome substrates, single lab, directly demonstrated substrate preference\",\n      \"pmids\": [\"26902486\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SET7 localizes to distinct cytoplasmic foci adjacent to the nucleus in erythrocytic stage and liver stage parasites, and is distributed throughout the cytoplasm in salivary gland sporozoites, as determined by direct cellular imaging.\",\n      \"method\": \"Cellular localization by fluorescence imaging across multiple parasite life cycle stages\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment, multiple life cycle stages examined, single lab, no functional consequence directly linked to localization\",\n      \"pmids\": [\"26902486\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Prokaryotic expression of the putative active domain of SET7 did not yield detectable HKMT activity towards recombinant P. falciparum histones (negative result); however, expression in a eukaryotic in vitro system showed HKMT activity towards H3.\",\n      \"method\": \"Prokaryotic and eukaryotic in vitro expression systems; HKMT activity assay with recombinant histones\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro activity assay, single lab, limited detail on which specific SET protein gave H3 activity; abstract is broad across multiple SET proteins\",\n      \"pmids\": [\"18299133\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SET7 was identified as a proximity interactor of PfSAMS (S-adenosylmethionine synthetase), the enzyme that synthesizes the methyl donor SAM, by proximity-dependent biotin identification (BioID) proteomics, placing SET7 within the SAM-dependent methylation network in blood-stage parasites.\",\n      \"method\": \"Proximity-dependent biotin identification (BioID) / proximity ligation proteomics\",\n      \"journal\": \"Microorganisms\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single proximity-ligation proteomics screen, no reciprocal validation, single lab; SET7 is one of 1114 identified interactors\",\n      \"pmids\": [\"35889137\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SET7 transcript is destabilized in the absence of the translational repressors DOZI and CITH in gametocytes, indicating that SET7 mRNA is subject to translational repression in gametocytes and may have a role in epigenetic control of the ookinete.\",\n      \"method\": \"Transcriptome analysis (suppression subtractive hybridization and RT-PCR) comparing wild-type and DOZI/CITH knockout gametocytes\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect evidence from transcript-level analysis in DOZI/CITH knockouts, no direct functional validation of SET7 translational repression, single method\",\n      \"pmids\": [\"23586929\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"SET7 (PF3D7_1115200) is a cytoplasmic, AdoMet-dependent histone H3 lysine methyltransferase that methylates H3K4 and H3K9 (and to a lesser extent H3K36) preferentially on nucleosomes bearing pre-existing H3K14 acetylation; it localizes to distinct cytoplasmic foci adjacent to the nucleus in erythrocytic and liver stage parasites and throughout the cytoplasm in salivary gland sporozoites, and its mRNA is subject to translational repression by DOZI/CITH in gametocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SET7 (PF3D7_1115200) is an AdoMet-dependent histone H3 lysine methyltransferase of Plasmodium falciparum that methylates H3K4 and H3K9, and to a lesser extent H3K36, as established by steady-state kinetic analysis of recombinant enzyme [#0]. Its activity is context-dependent: SET7 preferentially methylates nucleosomes carrying pre-existing H3K14 acetylation, defining a histone crosstalk in which H3K14ac primes SET7-mediated H3K4/K9 methylation [#1]. Consistent with dependence on the methyl donor SAM, SET7 was recovered as a proximity interactor of the S-adenosylmethionine synthetase PfSAMS, placing it within the parasite's SAM-dependent methylation network [#4]. SET7 localizes not to the nucleus but to distinct cytoplasmic foci adjacent to the nucleus in erythrocytic and liver stages, and throughout the cytoplasm in salivary gland sporozoites [#2], and its transcript is destabilized in the absence of the translational repressors DOZI and CITH in gametocytes, indicating stage-specific translational control [#5]. Beyond these enzymatic, localization, and regulatory observations, the in vivo chromatin targets and functional consequences of SET7 activity have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"The question of whether SET7 is catalytically active as a histone methyltransferase was first addressed by testing recombinant expression systems, showing that folding context matters for its activity.\",\n      \"evidence\": \"Prokaryotic vs eukaryotic in vitro expression of the putative active domain and HKMT assay against recombinant histones\",\n      \"pmids\": [\"18299133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Abstract is broad across multiple SET proteins; specific attribution of H3 activity to SET7 is limited\",\n        \"No lysine-residue specificity established at this stage\",\n        \"No cellular or in vivo confirmation of activity\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Full biochemical reconstitution established SET7 as a bona fide AdoMet-dependent H3 methyltransferase and defined its residue specificity, resolving what earlier expression tests left ambiguous.\",\n      \"evidence\": \"In vitro steady-state kinetics with recombinant purified enzyme testing multiple lysine substrates\",\n      \"pmids\": [\"26902486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo H3K4/K9/K36 targets and genomic distribution not mapped\",\n        \"Physiological relevance of the minor H3K36 activity unclear\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"By using nucleosomes bearing defined pre-existing modifications, the study showed SET7 is regulated by histone crosstalk, requiring H3K14 acetylation to efficiently methylate its targets.\",\n      \"evidence\": \"In vitro assay with recombinant SET7 on modified nucleosome substrates\",\n      \"pmids\": [\"26902486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The writer enzyme(s) generating H3K14ac in vivo not identified in this corpus\",\n        \"Whether the crosstalk operates on chromatin in living parasites untested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Cellular imaging addressed where SET7 acts, unexpectedly placing a histone methyltransferase in cytoplasmic foci rather than the nucleus and revealing stage-dependent redistribution.\",\n      \"evidence\": \"Fluorescence imaging across erythrocytic, liver, and sporozoite stages\",\n      \"pmids\": [\"26902486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How a cytoplasmic enzyme accesses chromatin substrates is unresolved\",\n        \"No functional consequence linked to the localization pattern\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Transcriptome analysis of DOZI/CITH knockout gametocytes placed SET7 under post-transcriptional control, implicating it in stage-specific epigenetic regulation during transmission.\",\n      \"evidence\": \"Suppression subtractive hybridization and RT-PCR comparing wild-type and DOZI/CITH knockout gametocytes\",\n      \"pmids\": [\"23586929\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Indirect transcript-level evidence; SET7 translational repression not directly demonstrated\",\n        \"No functional test of a SET7 role in the ookinete\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Proximity proteomics connected SET7 to the SAM-synthesizing enzyme PfSAMS, providing a spatial link to the methyl-donor supply consistent with its AdoMet dependence.\",\n      \"evidence\": \"BioID proximity-dependent biotin identification in blood-stage parasites\",\n      \"pmids\": [\"35889137\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single proximity screen without reciprocal validation; SET7 is one of >1000 hits\",\n        \"Direct or functional interaction with PfSAMS not established\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo genomic targets, chromatin context, and biological function of SET7-mediated methylation across the parasite life cycle remain to be defined.\",\n      \"evidence\": \"No direct in vivo functional or genome-wide localization study of SET7 in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No loss-of-function phenotype for SET7 reported\",\n        \"No genome-wide mapping of SET7-dependent H3K4/K9 marks\",\n        \"Mechanism reconciling cytoplasmic localization with histone substrates unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0018024\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0046975\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0046974\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008757\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006479\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0006556\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfSAMS (S-adenosylmethionine synthetase) — proximity interactor by BioID [#4]\"\n    ],\n    \"other_free_text\": [\n      \"AdoMet(SAM)-dependent enzyme; methylates H3K4 and H3K9 with lesser activity toward H3K36 [#0]\",\n      \"Prefers nucleosomes with pre-existing H3K14 acetylation, defining H3K14ac–H3K4/K9 crosstalk [#1]\",\n      \"Activity depends on eukaryotic expression context; prokaryotically expressed domain was inactive [#3]\",\n      \"Localizes to cytoplasmic foci adjacent to the nucleus (erythrocytic, liver stages) and throughout the cytoplasm in salivary gland sporozoites [#2]\",\n      \"SET7 transcript destabilized in DOZI/CITH knockout gametocytes, implying translational repression during transmission stages [#5]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1115200","name":null,"product":"histone-lysine N-methyltransferase SET7","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0932500","name":null,"product":"histone-lysine N-methyltransferase SET7, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0912700","name":null,"product":"histone-lysine N-methyltransferase SET7, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"SET7","evaluation":null}