{"gene":"PF3D7_0809900","run_date":"2026-09-08T16:26:55","timeline":{"discoveries":[{"year":2008,"finding":"JmjC1 (PF3D7_0809900) was identified by bioinformatic analysis as a JmjC-domain-containing protein in P. falciparum, predicted to function as a histone lysine demethylase capable of reversing trimethylated lysine residues, analogous to the JmjC-domain demethylase family in other eukaryotes.","method":"Bioinformatic/phylogenetic analysis of P. falciparum genome; no direct enzymatic assay of JmjC1 itself was reported","journal":"International journal for parasitology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no in vitro enzymatic assay of JmjC1 performed","pmids":["18299133"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"JmjC1 (PF3D7_0809900) was identified as the cognate demethylase of PfSET2, predicted to remove H3K36me3 marks deposited by PfSET2. Comparative genomic analysis showed JmjC1 is present in primate malaria parasites (P. falciparum, P. vivax, P. knowlesi) but absent from rodent malaria parasite genomes (P. berghei, P. yoelii, P. chabaudi), suggesting it is specific to primate parasites and functionally linked to PfSET2-mediated var gene regulation.","method":"Comparative genomics across six Plasmodium species; functional link to PfSET2 and H3K36me3 inferred from orthology, not direct enzymatic assay of JmjC1","journal":"PLoS pathogens","confidence":"Low","confidence_rationale":"Tier 4 / Weak — comparative genomics inference; no direct biochemical experiment performed on JmjC1 itself","pmids":["24391504"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium vivax","strain":""},{"species":"Plasmodium knowlesi","strain":""}]},{"year":2020,"finding":"JmjC1 (PF3D7_0809900) is one of three JmjC-domain-containing proteins in P. falciparum (alongside PfJmjC2 and PfJmj3). Residues required for iron and 2-oxoglutarate (2-OG) binding and substrate binding in mammalian Jumonji enzymes are conserved in PfJmjC1. Pharmacological inhibition of P. falciparum Jumonji demethylases with pan-JmjC inhibitors (JIB-04, GSK-J4, ML324, SD-70) killed asexual blood stage parasites and blocked gametocyte development, with increased trimethylated lysine marks on histones in late-stage parasites consistent with demethylase inhibition. PfJmj3 (not PfJmjC1) was directly demonstrated to convert 2-oxoglutarate to succinate in an iron-dependent manner, and this activity was inhibited by JIB-04.","method":"Sequence alignment (conservation of catalytic residues); asexual parasite growth inhibition assay (3D7, Dd2); gametocyte/gamete formation assay; histone trimethylation immunoassay; in vitro enzymatic assay of PfJmj3 catalytic activity (2-OG to succinate conversion)","journal":"ACS infectious diseases","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — conservation of catalytic residues shown by alignment for JmjC1; direct enzymatic assay performed on PfJmj3 only; pharmacological phenotypes apply to the JmjC family collectively; single lab, multiple methods but JmjC1-specific biochemistry not individually resolved","pmids":["32272012"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"Dd2"}]},{"year":2021,"finding":"In stage II gametocytes, the jmjc1 locus (PF3D7_0809900) is enriched for H3K36me2 and H3K36me3 upstream of the transcription start site, a pattern not seen in pre- or post-stage II gametocytes, correlating with transcriptional repression of jmjc1 at this stage. This H3K36me2&3-mediated repression of jmjc1 was proposed as a mechanism to safeguard the integrity of H3K36 methylation and associated transcriptional repression during early gametocyte development.","method":"Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) for H3K36me2 and H3K36me3 in stage-specific gametocytes; correlation with gene expression data","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP-seq directly demonstrates H3K36me2&3 enrichment at jmjc1 locus in stage II gametocytes with stage-specificity; single lab, single method; functional consequence (repression) inferred from mark association, not confirmed by loss-of-function","pmids":["33794978"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PfJmjC1 (PF3D7_0809900) is reported to be active on H3K9me2/3 and H3K36me3 substrates, while PfJmj3 is specific for H3K36me3. This substrate specificity is cited from prior literature (Matthews et al., 2020 and Cui et al., 2008a) in a review context.","method":"Cited from prior literature in a review; not a new direct experiment in this paper","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — review paper citing prior work; no new experiment performed; substrate specificity attributed to cited studies not directly available in this corpus","pmids":["35433676"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PfJmjC1 (PF3D7_0809900) is reported to be active on H3K9me2/3 and also H3K36me3, placing it in the JMJD/KDM4-related class of demethylases. This specificity is cited as an established property and used to rationalize inhibitor design targeting Plasmodium JmjC enzymes as structurally distinct from human KDM4B.","method":"Cited prior experimental data in the context of a medicinal chemistry study; no new direct experiment on JmjC1 performed","journal":"Chembiochem : a European journal of chemical biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — cited claim in a chemistry paper, no new experiment on JmjC1 itself","pmids":["36106425"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"JmjC1 (PF3D7_0809900) has syntenic orthologs throughout the Laverania subgenus and also in P. vivax and the bird parasite P. gallinaceum, but is absent from rodent malaria parasite genomes, suggesting its origin predates the root of the Plasmodium genus and that its functions are not restricted to var gene regulation.","method":"Comparative genomic synteny analysis across Plasmodium species and Laverania subgenus members","journal":"BMC ecology and evolution","confidence":"Low","confidence_rationale":"Tier 4 / Weak — comparative genomics only, no functional experiment","pmids":["34238209"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_0809900 (JmjC1) is a JmjC-domain-containing histone lysine demethylase in P. falciparum that conserves the iron- and 2-oxoglutarate-binding residues required for Jumonji catalysis; it is reported to demethylate H3K9me2/3 and H3K36me3 (substrate specificity attributed to prior literature), is absent from rodent but present in primate and avian malaria parasites, and is itself transcriptionally repressed in stage II gametocytes via H3K36me2/3 enrichment at its locus — but direct in vitro enzymatic characterization of JmjC1 specifically has not been reported in the available literature."},"narrative":{"mechanistic_narrative":"PF3D7_0809900 (JmjC1) is a predicted JmjC-domain histone lysine demethylase of P. falciparum that conserves the iron- and 2-oxoglutarate-binding and substrate-binding residues characteristic of the mammalian Jumonji enzyme family [PMID:18299133, PMID:32272012]. It is one of three JmjC-domain proteins in the parasite, and pharmacological inhibition of the P. falciparum Jumonji demethylases as a group with pan-JmjC inhibitors killed asexual blood-stage parasites and blocked gametocyte development, accompanied by increased trimethylated histone lysine marks consistent with loss of demethylase activity [PMID:32272012]. Comparative genomics places JmjC1 in primate and avian malaria parasites (P. falciparum, P. vivax, P. knowlesi, P. gallinaceum) but not in rodent malaria parasites, an evolutionary distribution linked to its functional coupling with PfSET2-deposited H3K36me3 [PMID:24391504, PMID:34238209]. Its own locus is repressed in stage II gametocytes through stage-specific H3K36me2/3 enrichment upstream of the transcription start site, integrating JmjC1 into the H3K36-methylation regulatory circuit during early gametocyte development [PMID:33794978]. Direct in vitro enzymatic characterization of JmjC1 specifically — including biochemical confirmation of its substrate specificity — has not been reported in the available corpus; catalytic activity was demonstrated for the sibling PfJmj3, not for JmjC1 [PMID:32272012].","teleology":[{"year":2008,"claim":"The question of whether P. falciparum encodes enzymes capable of removing histone lysine methylation was first addressed by identifying JmjC1 as a candidate JmjC-domain demethylase, establishing that active histone demethylation was plausible in the parasite.","evidence":"Bioinformatic/phylogenetic analysis of the P. falciparum genome; no direct enzymatic assay of JmjC1 performed","pmids":["18299133"],"confidence":"Low","gaps":["Computational prediction only; no in vitro demethylase assay of JmjC1","No substrate identified experimentally","No cellular localization or expression data"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"To connect JmjC1 to a defined chromatin pathway, comparative genomics proposed it as the cognate demethylase counteracting PfSET2-deposited H3K36me3 and showed it is restricted to primate malaria parasites, implicating it in var gene regulation.","evidence":"Comparative genomics across six Plasmodium species; functional link to PfSET2/H3K36me3 inferred from orthology, not direct assay of JmjC1","pmids":["24391504"],"confidence":"Low","gaps":["Enzyme-substrate link to H3K36me3 inferred from orthology, not demonstrated for JmjC1","No loss-of-function evidence for a role in var gene regulation","Functional consequence of primate-specific distribution untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium vivax","strain":""},{"species":"Plasmodium knowlesi","strain":""}]},{"year":2020,"claim":"Whether the parasite Jumonji enzymes are catalytically competent and druggable was tested; JmjC1 was shown to conserve the catalytic iron/2-OG residues, and pan-JmjC inhibition killed asexual parasites and blocked gametocytes with rising histone trimethylation, though direct catalysis was proven only for the sibling PfJmj3.","evidence":"Sequence alignment for JmjC1 catalytic residues; asexual growth (3D7, Dd2) and gametocyte assays with pan-JmjC inhibitors; histone trimethylation immunoassay; in vitro 2-OG-to-succinate assay of PfJmj3 only","pmids":["32272012"],"confidence":"Medium","gaps":["JmjC1-specific enzymatic activity not directly measured; catalysis shown for PfJmj3 only","Inhibitor phenotypes apply to the JmjC family collectively, not JmjC1 alone","No genetic knockout to attribute phenotypes to JmjC1"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"Dd2"}]},{"year":2021,"claim":"How JmjC1 itself is regulated across the life cycle was addressed by mapping histone marks at its locus, revealing stage II gametocyte-specific H3K36me2/3 enrichment upstream of its TSS correlating with transcriptional repression, embedding JmjC1 within a self-referential H3K36 regulatory circuit.","evidence":"ChIP-seq for H3K36me2/me3 in stage-specific gametocytes correlated with expression data","pmids":["33794978"],"confidence":"Medium","gaps":["Repression inferred from mark association, not confirmed by loss-of-function","Mechanism depositing H3K36me2/3 at jmjc1 not defined","Functional consequence of jmjc1 repression for gametocytes untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"The evolutionary breadth of JmjC1 was refined by synteny analysis showing conservation across Laverania, P. vivax, and the avian parasite P. gallinaceum but loss in rodent parasites, arguing its origin predates the Plasmodium root and its functions extend beyond var gene regulation.","evidence":"Comparative genomic synteny analysis across Plasmodium species and Laverania members","pmids":["34238209"],"confidence":"Low","gaps":["Comparative genomics only; no functional experiment","Additional (non-var) functions proposed but not defined","No mechanistic basis for loss in rodent parasites"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Reviews consolidated JmjC1's presumed substrate specificity, citing prior work that it acts on H3K9me2/3 and H3K36me3 and grouping it with the JMJD/KDM4-related demethylases to rationalize antimalarial inhibitor design, without adding new experimental evidence on JmjC1.","evidence":"Substrate specificity cited from prior literature in review and medicinal-chemistry contexts; no new experiment on JmjC1","pmids":["35433676","36106425"],"confidence":"Low","gaps":["Substrate specificity attributed to cited studies, not independently demonstrated in this corpus","No structural model of JmjC1","No direct enzyme kinetics or inhibitor selectivity data for JmjC1"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The central open question is direct biochemical demonstration of JmjC1's own demethylase activity and substrate specificity, and genetic dissection of its role in var gene regulation and gametocyte development independent of its sibling Jumonji enzymes.","evidence":"No timeline discovery provides JmjC1-specific in vitro catalysis or a targeted knockout phenotype","pmids":[],"confidence":"Low","gaps":["No purified-enzyme demethylase assay for JmjC1","No JmjC1-specific loss-of-function phenotype","No structure or defined interaction partners for JmjC1"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFSET2 (PROPOSED FUNCTIONAL/ENZYMATIC COUNTERPART, INFERRED FROM ORTHOLOGY [#1])"],"other_free_text":["One of three JmjC-domain proteins in P. falciparum (alongside PfJmjC2 and PfJmj3); direct catalytic activity was shown for PfJmj3, not JmjC1 [#2].","Conserves iron-, 2-oxoglutarate- and substrate-binding residues of mammalian Jumonji demethylases by sequence alignment [#2].","Reported (via cited prior literature in reviews) to act on H3K9me2/3 and H3K36me3, in the JMJD/KDM4-related class [#4, #5].","Its own locus (jmjc1) is repressed in stage II gametocytes via upstream H3K36me2/3 enrichment [#3].","Present in primate (P. falciparum, P. vivax, P. knowlesi) and avian (P. gallinaceum) malaria parasites and across the Laverania subgenus, but absent from rodent malaria parasites [#1, #6].","Pan-JmjC inhibitors (JIB-04, GSK-J4, ML324, SD-70) kill asexual parasites and block gametocyte development, but this phenotype is attributed to the JmjC family collectively, not JmjC1 alone [#2]."]}},"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":"42115185","id":"","title":"Global-scale population genetic analysis of Plasmodium falciparum identifies region-specific patterns of malaria parasite adaptation.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42115185","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["JmjC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38347549","id":"","title":"Epigenetic regulation as a therapeutic target in the malaria parasite Plasmodium falciparum.","date":"2024","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/38347549","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["JmjC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39738010","id":"","title":"Genomic analysis of global Plasmodium vivax populations reveals insights into the evolution of drug resistance.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39738010","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["JmjC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37208735","id":"","title":"Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolates.","date":"2023","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/37208735","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["JmjC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34238209","id":"","title":"Evolution of transcriptional control of antigenic variation and virulence in human and ape malaria parasites.","date":"2021","source":"BMC ecology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/34238209","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["JmjC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"36106425","id":"","title":"New Transmission-Selective Antimalarial Agents through Hit-to-Lead Optimization of 2-([1,1'-Biphenyl]-4-carboxamido)benzoic Acid Derivatives.","date":"2022","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/36106425","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["JmjC1"],"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":["JmjC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33794978","id":"","title":"H3K36 methylation reprograms gene expression to drive early gametocyte development in Plasmodium falciparum.","date":"2021","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/33794978","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["JmjC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32272012","id":"","title":"Disruption of the Plasmodium falciparum Life Cycle through Transcriptional Reprogramming by Inhibitors of Jumonji Demethylases.","date":"2020","source":"ACS infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/32272012","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["JmjC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31737048","id":"","title":"Genome-Wide Analysis of Genetic Diversity in Plasmodium falciparum Isolates From China-Myanmar Border.","date":"2019","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31737048","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["JmjC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"24391504","id":"","title":"Recruitment of PfSET2 by RNA polymerase II to variant antigen encoding loci contributes to antigenic variation in P. falciparum.","date":"2014","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/24391504","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["JmjC1"],"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":["JmjC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23398820","id":"","title":"Horizontal gene transfer of epigenetic machinery and evolution of parasitism in the malaria parasite Plasmodium falciparum and other apicomplexans.","date":"2013","source":"BMC evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/23398820","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["JmjC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17564,"output_tokens":2505,"usd":0.045134,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7743,"output_tokens":3709,"usd":0.06572,"stage2_stop_reason":"end_turn"},"total_usd":0.110854,"stage1_batch_id":"msgbatch_01NE1MTa8x1hW7Lo4tAaNzY1","stage2_batch_id":"msgbatch_0141vaQdeFvbo2q39AinvXM9","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"JmjC1 (PF3D7_0809900) was identified by bioinformatic analysis as a JmjC-domain-containing protein in P. falciparum, predicted to function as a histone lysine demethylase capable of reversing trimethylated lysine residues, analogous to the JmjC-domain demethylase family in other eukaryotes.\",\n      \"method\": \"Bioinformatic/phylogenetic analysis of P. falciparum genome; no direct enzymatic assay of JmjC1 itself was reported\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no in vitro enzymatic assay of JmjC1 performed\",\n      \"pmids\": [\"18299133\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JmjC1 (PF3D7_0809900) was identified as the cognate demethylase of PfSET2, predicted to remove H3K36me3 marks deposited by PfSET2. Comparative genomic analysis showed JmjC1 is present in primate malaria parasites (P. falciparum, P. vivax, P. knowlesi) but absent from rodent malaria parasite genomes (P. berghei, P. yoelii, P. chabaudi), suggesting it is specific to primate parasites and functionally linked to PfSET2-mediated var gene regulation.\",\n      \"method\": \"Comparative genomics across six Plasmodium species; functional link to PfSET2 and H3K36me3 inferred from orthology, not direct enzymatic assay of JmjC1\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — comparative genomics inference; no direct biochemical experiment performed on JmjC1 itself\",\n      \"pmids\": [\"24391504\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium vivax\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium knowlesi\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JmjC1 (PF3D7_0809900) is one of three JmjC-domain-containing proteins in P. falciparum (alongside PfJmjC2 and PfJmj3). Residues required for iron and 2-oxoglutarate (2-OG) binding and substrate binding in mammalian Jumonji enzymes are conserved in PfJmjC1. Pharmacological inhibition of P. falciparum Jumonji demethylases with pan-JmjC inhibitors (JIB-04, GSK-J4, ML324, SD-70) killed asexual blood stage parasites and blocked gametocyte development, with increased trimethylated lysine marks on histones in late-stage parasites consistent with demethylase inhibition. PfJmj3 (not PfJmjC1) was directly demonstrated to convert 2-oxoglutarate to succinate in an iron-dependent manner, and this activity was inhibited by JIB-04.\",\n      \"method\": \"Sequence alignment (conservation of catalytic residues); asexual parasite growth inhibition assay (3D7, Dd2); gametocyte/gamete formation assay; histone trimethylation immunoassay; in vitro enzymatic assay of PfJmj3 catalytic activity (2-OG to succinate conversion)\",\n      \"journal\": \"ACS infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — conservation of catalytic residues shown by alignment for JmjC1; direct enzymatic assay performed on PfJmj3 only; pharmacological phenotypes apply to the JmjC family collectively; single lab, multiple methods but JmjC1-specific biochemistry not individually resolved\",\n      \"pmids\": [\"32272012\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In stage II gametocytes, the jmjc1 locus (PF3D7_0809900) is enriched for H3K36me2 and H3K36me3 upstream of the transcription start site, a pattern not seen in pre- or post-stage II gametocytes, correlating with transcriptional repression of jmjc1 at this stage. This H3K36me2&3-mediated repression of jmjc1 was proposed as a mechanism to safeguard the integrity of H3K36 methylation and associated transcriptional repression during early gametocyte development.\",\n      \"method\": \"Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) for H3K36me2 and H3K36me3 in stage-specific gametocytes; correlation with gene expression data\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP-seq directly demonstrates H3K36me2&3 enrichment at jmjc1 locus in stage II gametocytes with stage-specificity; single lab, single method; functional consequence (repression) inferred from mark association, not confirmed by loss-of-function\",\n      \"pmids\": [\"33794978\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PfJmjC1 (PF3D7_0809900) is reported to be active on H3K9me2/3 and H3K36me3 substrates, while PfJmj3 is specific for H3K36me3. This substrate specificity is cited from prior literature (Matthews et al., 2020 and Cui et al., 2008a) in a review context.\",\n      \"method\": \"Cited from prior literature in a review; not a new direct experiment in this paper\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — review paper citing prior work; no new experiment performed; substrate specificity attributed to cited studies not directly available in this corpus\",\n      \"pmids\": [\"35433676\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PfJmjC1 (PF3D7_0809900) is reported to be active on H3K9me2/3 and also H3K36me3, placing it in the JMJD/KDM4-related class of demethylases. This specificity is cited as an established property and used to rationalize inhibitor design targeting Plasmodium JmjC enzymes as structurally distinct from human KDM4B.\",\n      \"method\": \"Cited prior experimental data in the context of a medicinal chemistry study; no new direct experiment on JmjC1 performed\",\n      \"journal\": \"Chembiochem : a European journal of chemical biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — cited claim in a chemistry paper, no new experiment on JmjC1 itself\",\n      \"pmids\": [\"36106425\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JmjC1 (PF3D7_0809900) has syntenic orthologs throughout the Laverania subgenus and also in P. vivax and the bird parasite P. gallinaceum, but is absent from rodent malaria parasite genomes, suggesting its origin predates the root of the Plasmodium genus and that its functions are not restricted to var gene regulation.\",\n      \"method\": \"Comparative genomic synteny analysis across Plasmodium species and Laverania subgenus members\",\n      \"journal\": \"BMC ecology and evolution\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — comparative genomics only, no functional experiment\",\n      \"pmids\": [\"34238209\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_0809900 (JmjC1) is a JmjC-domain-containing histone lysine demethylase in P. falciparum that conserves the iron- and 2-oxoglutarate-binding residues required for Jumonji catalysis; it is reported to demethylate H3K9me2/3 and H3K36me3 (substrate specificity attributed to prior literature), is absent from rodent but present in primate and avian malaria parasites, and is itself transcriptionally repressed in stage II gametocytes via H3K36me2/3 enrichment at its locus — but direct in vitro enzymatic characterization of JmjC1 specifically has not been reported in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0809900 (JmjC1) is a predicted JmjC-domain histone lysine demethylase of P. falciparum that conserves the iron- and 2-oxoglutarate-binding and substrate-binding residues characteristic of the mammalian Jumonji enzyme family [#0, #2]. It is one of three JmjC-domain proteins in the parasite, and pharmacological inhibition of the P. falciparum Jumonji demethylases as a group with pan-JmjC inhibitors killed asexual blood-stage parasites and blocked gametocyte development, accompanied by increased trimethylated histone lysine marks consistent with loss of demethylase activity [#2]. Comparative genomics places JmjC1 in primate and avian malaria parasites (P. falciparum, P. vivax, P. knowlesi, P. gallinaceum) but not in rodent malaria parasites, an evolutionary distribution linked to its functional coupling with PfSET2-deposited H3K36me3 [#1, #6]. Its own locus is repressed in stage II gametocytes through stage-specific H3K36me2/3 enrichment upstream of the transcription start site, integrating JmjC1 into the H3K36-methylation regulatory circuit during early gametocyte development [#3]. Direct in vitro enzymatic characterization of JmjC1 specifically — including biochemical confirmation of its substrate specificity — has not been reported in the available corpus; catalytic activity was demonstrated for the sibling PfJmj3, not for JmjC1 [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"The question of whether P. falciparum encodes enzymes capable of removing histone lysine methylation was first addressed by identifying JmjC1 as a candidate JmjC-domain demethylase, establishing that active histone demethylation was plausible in the parasite.\",\n      \"evidence\": \"Bioinformatic/phylogenetic analysis of the P. falciparum genome; no direct enzymatic assay of JmjC1 performed\",\n      \"pmids\": [\"18299133\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational prediction only; no in vitro demethylase assay of JmjC1\",\n        \"No substrate identified experimentally\",\n        \"No cellular localization or expression data\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"To connect JmjC1 to a defined chromatin pathway, comparative genomics proposed it as the cognate demethylase counteracting PfSET2-deposited H3K36me3 and showed it is restricted to primate malaria parasites, implicating it in var gene regulation.\",\n      \"evidence\": \"Comparative genomics across six Plasmodium species; functional link to PfSET2/H3K36me3 inferred from orthology, not direct assay of JmjC1\",\n      \"pmids\": [\"24391504\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Enzyme-substrate link to H3K36me3 inferred from orthology, not demonstrated for JmjC1\",\n        \"No loss-of-function evidence for a role in var gene regulation\",\n        \"Functional consequence of primate-specific distribution untested\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium vivax\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium knowlesi\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether the parasite Jumonji enzymes are catalytically competent and druggable was tested; JmjC1 was shown to conserve the catalytic iron/2-OG residues, and pan-JmjC inhibition killed asexual parasites and blocked gametocytes with rising histone trimethylation, though direct catalysis was proven only for the sibling PfJmj3.\",\n      \"evidence\": \"Sequence alignment for JmjC1 catalytic residues; asexual growth (3D7, Dd2) and gametocyte assays with pan-JmjC inhibitors; histone trimethylation immunoassay; in vitro 2-OG-to-succinate assay of PfJmj3 only\",\n      \"pmids\": [\"32272012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"JmjC1-specific enzymatic activity not directly measured; catalysis shown for PfJmj3 only\",\n        \"Inhibitor phenotypes apply to the JmjC family collectively, not JmjC1 alone\",\n        \"No genetic knockout to attribute phenotypes to JmjC1\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"How JmjC1 itself is regulated across the life cycle was addressed by mapping histone marks at its locus, revealing stage II gametocyte-specific H3K36me2/3 enrichment upstream of its TSS correlating with transcriptional repression, embedding JmjC1 within a self-referential H3K36 regulatory circuit.\",\n      \"evidence\": \"ChIP-seq for H3K36me2/me3 in stage-specific gametocytes correlated with expression data\",\n      \"pmids\": [\"33794978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Repression inferred from mark association, not confirmed by loss-of-function\",\n        \"Mechanism depositing H3K36me2/3 at jmjc1 not defined\",\n        \"Functional consequence of jmjc1 repression for gametocytes untested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The evolutionary breadth of JmjC1 was refined by synteny analysis showing conservation across Laverania, P. vivax, and the avian parasite P. gallinaceum but loss in rodent parasites, arguing its origin predates the Plasmodium root and its functions extend beyond var gene regulation.\",\n      \"evidence\": \"Comparative genomic synteny analysis across Plasmodium species and Laverania members\",\n      \"pmids\": [\"34238209\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Comparative genomics only; no functional experiment\",\n        \"Additional (non-var) functions proposed but not defined\",\n        \"No mechanistic basis for loss in rodent parasites\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reviews consolidated JmjC1's presumed substrate specificity, citing prior work that it acts on H3K9me2/3 and H3K36me3 and grouping it with the JMJD/KDM4-related demethylases to rationalize antimalarial inhibitor design, without adding new experimental evidence on JmjC1.\",\n      \"evidence\": \"Substrate specificity cited from prior literature in review and medicinal-chemistry contexts; no new experiment on JmjC1\",\n      \"pmids\": [\"35433676\", \"36106425\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Substrate specificity attributed to cited studies, not independently demonstrated in this corpus\",\n        \"No structural model of JmjC1\",\n        \"No direct enzyme kinetics or inhibitor selectivity data for JmjC1\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central open question is direct biochemical demonstration of JmjC1's own demethylase activity and substrate specificity, and genetic dissection of its role in var gene regulation and gametocyte development independent of its sibling Jumonji enzymes.\",\n      \"evidence\": \"No timeline discovery provides JmjC1-specific in vitro catalysis or a targeted knockout phenotype\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No purified-enzyme demethylase assay for JmjC1\",\n        \"No JmjC1-specific loss-of-function phenotype\",\n        \"No structure or defined interaction partners for JmjC1\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0032452\", \"supporting_discovery_ids\": [0, 2, 4, 5]},\n      {\"term_id\": \"GO:0051213\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005506\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0016706\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016577\", \"supporting_discovery_ids\": [0, 2, 4, 5]},\n      {\"term_id\": \"GO:0006338\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0045892\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfSET2 (proposed functional/enzymatic counterpart, inferred from orthology [#1])\"\n    ],\n    \"other_free_text\": [\n      \"One of three JmjC-domain proteins in P. falciparum (alongside PfJmjC2 and PfJmj3); direct catalytic activity was shown for PfJmj3, not JmjC1 [#2].\",\n      \"Conserves iron-, 2-oxoglutarate- and substrate-binding residues of mammalian Jumonji demethylases by sequence alignment [#2].\",\n      \"Reported (via cited prior literature in reviews) to act on H3K9me2/3 and H3K36me3, in the JMJD/KDM4-related class [#4, #5].\",\n      \"Its own locus (jmjc1) is repressed in stage II gametocytes via upstream H3K36me2/3 enrichment [#3].\",\n      \"Present in primate (P. falciparum, P. vivax, P. knowlesi) and avian (P. gallinaceum) malaria parasites and across the Laverania subgenus, but absent from rodent malaria parasites [#1, #6].\",\n      \"Pan-JmjC inhibitors (JIB-04, GSK-J4, ML324, SD-70) kill asexual parasites and block gametocyte development, but this phenotype is attributed to the JmjC family collectively, not JmjC1 alone [#2].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0809900","name":null,"product":"JmjC domain-containing protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1430800","name":null,"product":"JmjC domain-containing protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"JmjC1","evaluation":null}