{"gene":"PF3D7_0610400","run_date":"2026-09-08T12:51:26","timeline":{"discoveries":[{"year":1995,"finding":"The sequence of Plasmodium falciparum histone H3 (PF3D7_0610400) was determined, establishing its identity as a canonical histone H3 in this parasite.","method":"DNA sequencing / molecular cloning","journal":"Molecular and biochemical parasitology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single sequencing study, no functional follow-up described in abstract","pmids":["7723778"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"finding":"Plasmodium falciparum histone H3 was cloned and expressed as a recombinant protein; sequence analysis revealed that the apicomplexan H3 proteins harbor novel and rare features compared to other eukaryotes, establishing the existence of at least two H3 variants (H3 and H3.3) in this parasite.","method":"Molecular cloning, sequence analysis, recombinant protein expression","journal":"DNA sequence : the journal of DNA sequencing and mapping","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, sequence and expression only, no functional assay described in abstract","pmids":["14509838"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2004,"finding":"Recombinant PfGCN5 acetylates histone H3 (PF3D7_0610400) at lysine 8 and lysine 14 in vitro, establishing H3 as a substrate of PfGCN5 with site-specific modification at K8 and K14.","method":"In vitro HAT assay with recombinant PfGCN5 using free core histones as substrate, substrate-specific antibodies","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis-level specificity (antibody-confirmed sites), replicated in subsequent studies","pmids":["15075257"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"Mass spectrometry of P. falciparum histones identified acetylation of lysines and methylation of lysines and arginines in the N-terminus of histone H3 (PF3D7_0610400). Recombinant PfH3 was efficiently acetylated by both recombinant and native PfGCN5 at K9 and K14, confirming H3 as a substrate despite sequence divergence from mammalian H3 N-termini. H3-K9 acetylation increased in late trophozoite and schizont stages during intraerythrocytic development.","method":"Mass spectrometry of purified histones, in vitro acetyltransferase assay with recombinant PfH3 and PfGCN5, immunoblotting with acetylation-specific antibodies at multiple time points","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry identification of PTM sites plus in vitro reconstitution with recombinant proteins, multiple orthogonal methods in single study","pmids":["16410041"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"Curcumin treatment caused specific hypoacetylation of histone H3 (PF3D7_0610400) at K9 and K14 (but not H4 at K5, K8, K12, K16) in P. falciparum, consistent with inhibition of PfGCN5 HAT activity, as confirmed by in vitro HAT inhibition assays with recombinant PfGCN5.","method":"In vitro HAT assay with recombinant PfGCN5, nuclear HAT activity assay, acetylation-specific antibodies","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro assay plus cellular confirmation with specific antibodies, single lab, two orthogonal methods","pmids":["17145789"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"PfGCN5-mediated acetylation of histone H3 (PF3D7_0610400) at K9 (H3K9ac) is enriched at putative promoter regions of active genes in a stage-specific manner during erythrocytic development; H3K9ac and H3K9me3 marks on H3 act antagonistically as epigenetic markers of active and silent genes respectively, genome-wide.","method":"ChIP-on-chip (chromatin immunoprecipitation with microarray), real-time PCR, treatment with PfGCN5 inhibitor","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-on-chip with functional validation by inhibitor treatment and stage-specific PCR, replicated in multiple subsequent studies","pmids":["17449656"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"Trimethylation and dimethylation of histone H3 lysine 4 (H3K4me3/me2) on PF3D7_0610400 peaks in the 5' upstream region of transcribed var genes and acts as a bookmarking epigenetic mark during the poised state; H3K9me3 acts antagonistically to K4 methylation to establish stable var gene silencing, while H3K9 acetylation competes with H3K9 methylation in the 5' flanking region to repress or activate var gene expression.","method":"Chromatin immunoprecipitation (ChIP) with modification-specific antibodies, real-time PCR across var gene regions","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal ChIP mapping of multiple H3 PTMs across gene regions with functional interpretation, replicated across labs","pmids":["18028313"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"H3K9me3 on histone H3 (PF3D7_0610400) serves as an epigenetic mark controlling var gene transcription and antigenic variation, constituting a chromatin memory associated with mutually exclusive var gene expression.","method":"Chromatin immunoprecipitation (ChIP) with H3K9me3-specific antibodies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based localization of H3K9me3 at var gene loci, single lab, consistent with independent replication in companion studies","pmids":["17209011"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"finding":"Anacardic acid inhibits PfGCN5 HAT activity and induces hypoacetylation of histone H3 (PF3D7_0610400) at K9 and K14 (but not H4 at K5, K8, K12, K16), with ChIP-PCR confirming reduced H3K9 acetylation near promoters of downregulated genes, establishing H3K9/K14ac as functionally linked to active gene expression.","method":"In vitro HAT inhibition assay with recombinant PfGCN5, acetylation-specific antibodies, ChIP and real-time PCR, microarray gene expression","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution plus cellular ChIP and genome-wide transcriptomics, multiple orthogonal methods in single study","pmids":["18487348"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"finding":"Methyl marks were detected on K4, K9, and K36 of histone H3 (PF3D7_0610400) by site-specific methyl-lysine antibodies; two P. falciparum SET-domain protein domains expressed in a eukaryotic system showed histone methyltransferase activity towards H3 in vitro.","method":"Site-specific methyl-lysine antibodies, in vitro eukaryotic expression and HKMT activity assay","journal":"International journal for parasitology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro methyltransferase assay confirmed H3 as substrate, but the specific SET proteins responsible for each H3 site were not fully resolved in this study","pmids":["18299133"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"The chromodomain (CD) of PfHP1 binds specifically to di- and tri-methylated lysine 9 of histone H3 (PF3D7_0610400) but not to unmodified H3 or H3K4-methylated forms, establishing H3K9me2/3 as the recognition mark for PfHP1-mediated heterochromatin formation and var gene silencing.","method":"Recombinant protein binding assay (CD of PfHP1 vs. modified/unmodified H3 peptides), ChIP analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of binding specificity with recombinant domain plus ChIP validation in parasite, two orthogonal methods","pmids":["19270070"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"Mass spectrometry analysis of P. falciparum asexual stage histones revealed a general preponderance of H3/H4 acetylation and H3K4me3 on histone H3. ChIP-on-chip profiling showed H3K4me3 and H3K9ac on H3 are broadly distributed across euchromatic genome regions in asynchronous parasites, with stage-specific patterns: in rings they are homogeneous across genes, while in schizonts they are enriched at the 5' end of active genes.","method":"Mass spectrometry, ChIP-on-chip with H3, H3K4me3, H3K9me3, H3K9ac antibodies, synchronized parasite analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — MS identification of modifications plus genome-wide ChIP-on-chip in multiple parasite stages, orthogonal methods","pmids":["19497874"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"H3K9ac and H3K4me3 modifications on histone H3 (PF3D7_0610400) are preferentially deposited at H2A.Z-containing nucleosomes in euchromatic intergenic regions; H3K9ac at promoter regions correlates with transcriptional status dynamically throughout the intraerythrocytic cycle, while H3K4me3 shows stage-specific regulation peaking at trophozoite stage.","method":"Genome-wide ChIP with next-generation sequencing (ChIP-seq) for H2A.Z, H3K9ac, H3K4me3; RNA-seq at 8 time points; linear amplification library preparation","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq with temporal RNA-seq across 8 time points, multiple marks analyzed, independently consistent with prior and subsequent studies","pmids":["21187892"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"Recombinant P. falciparum histone H3 (PfH3/PF3D7_0610400) directly stimulated production of IL-8 and other inflammatory mediators by primary human endothelial cells via Src family kinases and p38 MAPK signaling, and induced endothelial permeability through a charge-dependent mechanism; these effects were abrogated by histone-specific antibodies and by recombinant human activated protein C, which proteolytically cleaved PfH3.","method":"Recombinant PfH3 treatment of primary human dermal microvascular endothelial cells, antibody blocking, kinase inhibitors, live cell imaging, activated protein C cleavage assay","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — recombinant protein functional assay with multiple orthogonal validations (antibody abrogation, protease cleavage, signaling pathway inhibitors), single lab","pmids":["22260922"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"PfSETvs-dependent trimethylation of histone H3 lysine 36 (H3K36me3) on PF3D7_0610400, present along the entire var gene body including the transcription start site, is required for silencing of var genes; knockout of PfSETvs abolished H3K36me3 at var genes and resulted in transcription of virtually all var genes simultaneously.","method":"PfSETvs knockout by targeted disruption, ChIP with H3K36me3-specific antibodies, RNA-seq, flow cytometry, immunofluorescence","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with genome-wide ChIP and transcriptomics, multiple orthogonal readouts, published in high-impact journal","pmids":["23823717"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"Fourteen phosphorylation sites on histone H3 (PF3D7_0610400) and other histones were detected by LC-MS/MS in P. falciparum asexual blood stages; Pf14-3-3I was identified as a phospho-H3 reader that preferentially binds H3S28ph over H3S10ph, independent of modification of neighboring residues.","method":"LC-MS/MS with phosphopeptide enrichment, recombinant Pf14-3-3I protein binding to purified parasite histones, ITC with H3 phosphopeptides, in silico structural analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS-based PTM identification plus in vitro binding assay with purified recombinant protein and ITC quantification, multiple orthogonal methods","pmids":["23308157"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"Genome-wide ChIP-on-chip mapping of twelve histone modifications including H3K9ac, H3K14ac, H3K56ac, H3K4me3, and H3K79me3 on histone H3 (PF3D7_0610400) throughout the P. falciparum IDC showed dynamic stage-specific enrichment; H3 acetylations correlate with transcript levels and show differential affinity to genomic regions. H4K8ac occupies predominantly promoter regions while H3 marks occur at 5' ends of coding sequences, with promoter occupancy of H4K8ac retained when ectopically inserted at a different locus.","method":"ChIP-on-chip with modification-specific antibodies across erythrocytic stages, ectopic locus insertion","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-on-chip for 12 histone marks with functional ectopic insertion validation, multiple orthogonal methods","pmids":["23468622"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"PfBDP1 bromodomain protein binds to acetylated histone H3 (PF3D7_0610400) at transcriptional start sites of invasion-related genes; conditional PfBDP1 knockdown reduces expression of invasion genes and impairs parasite invasion.","method":"Conditional knockdown (DiCre or similar), ChIP-seq, co-immunoprecipitation, RNA-seq","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KD with clear invasion phenotype, ChIP-seq localization, Co-IP binding to acetylated H3, multiple orthogonal methods","pmids":["26067602"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"PfSET7 is an AdoMet-dependent histone methyltransferase that methylates histone H3 (PF3D7_0610400) at K4 and K9 (with highest activity towards these residues); PfSET7 displays specific substrate preference towards nucleosomes with pre-existing H3K14 acetylation.","method":"Recombinant PfSET7 expression and purification, in vitro methyltransferase assay with H3 substrates, steady-state kinetics, substrate preference assay with H3K14ac-containing nucleosomes","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — full enzymatic characterization in vitro with recombinant enzyme, steady-state kinetics, substrate specificity defined by nucleosome modifications","pmids":["26902486"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"A crystal structure of the PfGCN5 bromodomain in complex with the PCAF bromodomain inhibitor L-45 was solved, rationalizing selective binding to PCAF/GCN5 bromodomains; PfGCN5 bromodomain interaction with histone H3.3 (a variant) was disrupted in cells by L-45, but this experiment was performed with H3.3 (the variant), not canonical H3 (PF3D7_0610400).","method":"Co-crystal structure of PfGCN5-BRD with inhibitor, nanoBRET assay in cells","journal":"Angewandte Chemie (International ed. in English)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — crystal structure is of PfGCN5 bromodomain, not H3 itself; the cellular interaction tested was with H3.3 variant not canonical H3; indirect relevance to PF3D7_0610400","pmids":["27966810"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"Proteolytic clipping of the N-terminal tail of nucleosome-associated histone H3 (PF3D7_0610400) at amino acid position 21 occurs in P. falciparum via a cathepsin C-like activity present in nuclear parasite extracts; ectopically expressed clipped H3 (PfH3p-HA) is targeted to the nucleus, integrates into mononucleosomes, and ChIP-seq shows it is highly enriched upstream of six DNA replication/repair genes, demarcating a specific 1.5 kb chromatin island.","method":"Nuclear extract proteolytic clipping assay, ectopic expression of truncated H3-HA, ChIP-seq, subcellular fractionation/localization","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical clipping activity in nuclear extracts plus functional ectopic expression with ChIP-seq genome-wide localization, multiple orthogonal methods in single study","pmids":["30833341"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"H3K18ac and H3K27ac modifications on histone H3 (PF3D7_0610400) dynamically mark regulatory sequences upstream of genes during the asexual life cycle, co-localizing with PfAP2-I, PfBDP1, and PfH2A.Z at stably positioned nucleosomes within exposed DNA at active transcriptional start sites; transient transfection assays showed that sequences enriched for these marks possess promoter activity in schizont stages but no enhancer-like activity.","method":"ChIP-seq for H3K18ac, H3K27ac, H3K4me1, H3K27ac; integration with existing datasets; transient transfection promoter activity assays","journal":"Epigenetics & chromatin","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with functional validation by transfection assays, multiple marks analyzed, integration with independent datasets","pmids":["33225957"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"Plasmodium falciparum histone chaperone PfAsf1 specifically interacts with histone H3 (PF3D7_0610400) and H4 and deposits the H3/H4 dimer onto DNA to form disomes; critical residues of PfAsf1 involved in H3/H4 interaction were mapped by site-directed mutagenesis, and the crystal structure of PfAsf1 N-terminal domain was solved at 2.4 Å.","method":"X-ray crystallography of PfAsf1 (2.4 Å), co-immunoprecipitation/pulldown of PfAsf1 with P. falciparum H3/H4, in vitro nucleosome assembly (disome formation) assay, site-directed mutagenesis of PfAsf1","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus in vitro reconstitution of H3/H4 chaperone activity and mutagenesis of binding interface, multiple orthogonal methods","pmids":["33501928"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"The PfBDP1 bromodomain preferentially recognizes tetra-acetylated histone H4 and also weakly interacts with multi-acetylated H2A.Z in addition to previously reported acetylated histone H3 (PF3D7_0610400); a crystal structure of PfBDP1-BRD reveals a unique binding mechanism distinct from human bromodomain families.","method":"Crystal structure of PfBDP1 bromodomain, solution NMR spectroscopy, ITC binding assays with acetylated histone peptides","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure plus NMR and ITC for binding, but interaction with canonical H3 (PF3D7_0610400) was a weaker/secondary finding compared to H4 in this study","pmids":["36328269"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"PfPRMT5 catalyzes symmetric dimethylation of histone H3 (PF3D7_0610400) at R2 (H3R2me2s) and R8 in vitro; genome-wide H3R2me2s marks invasion-related genes and other loci, and PfPRMT5 disruption depletes H3R2me2s and reduces invasion efficiency and invasion gene transcription.","method":"In vitro methyltransferase assay with recombinant PfPRMT5, ChIP-seq for H3R2me2s, conditional disruption of PfPRMT5, transcriptomics, interactome (Co-IP/MS)","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of H3 methylation plus genome-wide ChIP-seq and genetic disruption with defined phenotype, multiple orthogonal methods","pmids":["37349497"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"P. falciparum histone H3 (PF3D7_0610400) is the canonical nucleosomal histone H3 whose N-terminal tail undergoes extensive post-translational modifications — including acetylation at K9 and K14 (written by PfGCN5), methylation at K4, K9, K36 and K79 (by distinct SET-domain methyltransferases including PfSETvs for K36me3 and PfSET7 for K4/K9), symmetric dimethylation at R2 and R8 (by PfPRMT5), phosphorylation at S10 and S28 (read by Pf14-3-3I), and proteolytic N-terminal clipping (by a cathepsin C-like nuclear activity); these marks collectively determine heterochromatin assembly at virulence and subtelomeric loci (via H3K9me3 recognized by PfHP1), activate or repress var gene expression (via H3K36me3, H3K4me3, H3K9ac/me3 balance), direct invasion gene expression (via H3K9ac/H3R2me2s recognized by PfBDP1), and regulate DNA replication gene chromatin through incorporation of clipped H3, while extracellular H3 released from lysed infected erythrocytes directly induces endothelial inflammation and permeability through Src/p38 MAPK signaling."},"narrative":{"mechanistic_narrative":"PF3D7_0610400 is the canonical nucleosomal histone H3 of Plasmodium falciparum, first identified by sequencing as a divergent apicomplexan H3 [PMID:7723778, PMID:14509838], and it functions as the central substrate scaffold on which the parasite's chromatin-based gene regulation is written and read. Its N-terminal tail is subject to extensive, enzyme-specific modification: PfGCN5 acetylates K9 and K14 [PMID:15075257, PMID:16410041], distinct SET-domain methyltransferases including PfSET7 (K4/K9) and PfSETvs (K36me3) methylate lysine residues [PMID:23823717, PMID:26902486], PfPRMT5 symmetrically dimethylates R2 and R8 [PMID:37349497], and the tail is phosphorylated at multiple serines [PMID:23308157] and proteolytically clipped at position 21 by a nuclear cathepsin C-like activity [PMID:30833341]. These marks partition the genome into functional chromatin states: H3K9ac and H3K4me3 broadly mark active euchromatin and 5' ends of transcribed genes in a stage-specific manner during intraerythrocytic development [PMID:17449656, PMID:19497874, PMID:21187892], while H3K9me3 recruits the PfHP1 chromodomain to establish heterochromatin and enforce mutually exclusive var gene silencing and antigenic variation [PMID:17209011, PMID:19270070]. PfSETvs-dependent H3K36me3 across var gene bodies is required to keep var genes silent [PMID:23823717], and reader proteins including PfBDP1 (acetyl-H3) and Pf14-3-3I (phospho-H3S28) couple these marks to invasion gene expression and downstream signaling [PMID:23308157, PMID:26067602, PMID:37349497]. Clipped H3 integrates into mononucleosomes and demarcates a chromatin island upstream of DNA replication/repair genes [PMID:30833341], and extracellular recombinant H3 released from infected erythrocytes directly triggers endothelial inflammation and permeability through Src-family kinase and p38 MAPK signaling [PMID:22260922].","teleology":[{"year":1995,"claim":"Establishing the primary sequence of parasite H3 was the necessary first step to define this protein as a bona fide histone H3 in P. falciparum.","evidence":"DNA sequencing/molecular cloning of the H3 gene","pmids":["7723778"],"confidence":"Low","gaps":["Sequence only, no functional characterization","Variant composition of the H3 family not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"claim":"Recombinant expression and sequence analysis showed apicomplexan H3 has rare/novel features and revealed at least two H3 variants (H3 and H3.3), framing the question of whether the divergent tail could still serve as a modification substrate.","evidence":"Molecular cloning, sequence analysis, recombinant protein expression","pmids":["14509838"],"confidence":"Low","gaps":["No enzymatic modification assays","Functional distinction between H3 and H3.3 not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"claim":"Identifying PfGCN5 as the enzyme acetylating H3 at K9/K14 and mapping methyl/acetyl marks by mass spectrometry established that despite tail divergence, parasite H3 carries a conventional repertoire of PTMs deposited by defined writers.","evidence":"In vitro HAT assays with recombinant PfGCN5, mass spectrometry of purified histones, acetylation-specific antibodies, stage timepoints (builds on earlier K8/K14 assignment)","pmids":["15075257","16410041"],"confidence":"High","gaps":["Site nomenclature (K8 vs K9) reconciliation across studies","In vivo requirement of PfGCN5 for these marks not tested genetically"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"claim":"Chemical inhibition of PfGCN5 (curcumin, anacardic acid) causing specific H3K9/K14 hypoacetylation with reduced expression of target genes linked H3 acetylation causally to active transcription and to antiparasitic action.","evidence":"In vitro HAT inhibition assays, acetylation-specific antibodies, ChIP-PCR, microarray transcriptomics","pmids":["17145789","18487348"],"confidence":"Medium","gaps":["Inhibitors may have off-target effects beyond PfGCN5","Direct genetic knockout of PfGCN5 not performed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"claim":"Genome-wide ChIP mapping established that H3K9ac marks active promoters while H3K9me3 marks silent loci, and that H3K4/K9 methylation and H3K9 acetylation act antagonistically to control var gene switching — defining H3 as the carrier of epigenetic memory for antigenic variation.","evidence":"ChIP-on-chip, ChIP-PCR with modification-specific antibodies across var loci and genome-wide, site-specific methyl-lysine antibodies with in vitro SET-domain HKMT assays","pmids":["17449656","18028313","17209011","18299133"],"confidence":"High","gaps":["Which specific SET enzymes deposit each methyl mark not fully resolved here","Mechanism enforcing mutual exclusivity not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"claim":"Demonstrating that the PfHP1 chromodomain binds H3K9me2/3 but not unmodified or H3K4me forms identified the direct reader that translates the H3K9me mark into heterochromatin formation and var silencing.","evidence":"Recombinant PfHP1 chromodomain binding to modified H3 peptides, ChIP validation in parasites","pmids":["19270070"],"confidence":"High","gaps":["Downstream effectors recruited by PfHP1 not defined here","Structural basis of specificity not solved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"claim":"High-resolution ChIP-seq with temporal RNA-seq linked H3K9ac/H3K4me3 dynamics to H2A.Z-containing euchromatic nucleosomes and to transcriptional timing across the intraerythrocytic cycle, integrating H3 marks into genome-wide chromatin architecture.","evidence":"ChIP-seq for H2A.Z, H3K9ac, H3K4me3; RNA-seq at 8 timepoints; mass spectrometry","pmids":["21187892","19497874"],"confidence":"High","gaps":["Causality between mark deposition and transcription not tested by perturbation","Reader proteins for these euchromatic marks not identified here"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Showing that extracellular recombinant PfH3 activates endothelial inflammation and permeability via Src/p38 MAPK signaling revealed a non-chromatin, pathogenic role for H3 released from lysed infected cells in malaria pathology.","evidence":"Recombinant PfH3 treatment of endothelial cells, antibody blocking, kinase inhibitors, live imaging, activated protein C cleavage","pmids":["22260922"],"confidence":"High","gaps":["Endothelial receptor for extracellular H3 not identified","In vivo contribution to malaria pathology not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"PfSETvs knockout abolishing H3K36me3 and de-repressing all var genes simultaneously established H3K36me3 as a required silencing mark and defined the enzyme responsible, advancing the mechanism of mutually exclusive var expression.","evidence":"Targeted PfSETvs knockout, ChIP with H3K36me3 antibodies, RNA-seq, flow cytometry, immunofluorescence","pmids":["23823717"],"confidence":"High","gaps":["How H3K36me3 mechanistically silences var bodies not defined","Reader of H3K36me3 not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"Detection of 14 histone phosphosites and identification of Pf14-3-3I as a phospho-H3S28 reader, plus genome-wide mapping of twelve H3 acetyl/methyl marks, expanded the H3 PTM landscape and its stage-specific genomic distribution.","evidence":"LC-MS/MS phosphoproteomics, recombinant Pf14-3-3I binding and ITC, ChIP-on-chip for twelve marks, ectopic locus insertion","pmids":["23308157","23468622"],"confidence":"High","gaps":["Kinases depositing H3S10/S28ph not identified","Functional consequence of Pf14-3-3I binding not tested by perturbation"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"PfBDP1 binding to acetylated H3 at invasion gene start sites, with knockdown impairing invasion, connected H3 acetylation reading to the invasion transcriptional program and a defined biological phenotype.","evidence":"Conditional PfBDP1 knockdown, ChIP-seq, Co-IP, RNA-seq","pmids":["26067602"],"confidence":"High","gaps":["Precise acetyl-H3 residues bound not fully mapped here","Whether PfBDP1 also reads other histones not addressed here"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"Enzymatic characterization of PfSET7 as an H3K4/K9 methyltransferase with preference for pre-existing H3K14ac established cross-talk between acetylation and methylation writing on the same H3 tail.","evidence":"Recombinant PfSET7 in vitro methyltransferase assays, steady-state kinetics, nucleosome substrate preference","pmids":["26902486"],"confidence":"High","gaps":["In vivo genomic targets of PfSET7 not mapped here","Relative contribution of PfSET7 vs other SET enzymes to K4/K9me not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"Discovery of cathepsin C-like N-terminal clipping of H3 at position 21 and mapping of clipped H3 to a chromatin island upstream of DNA replication/repair genes revealed a proteolytic modification mechanism distinct from side-chain PTMs.","evidence":"Nuclear extract clipping assay, ectopic expression of truncated H3-HA, ChIP-seq, subcellular fractionation","pmids":["30833341"],"confidence":"High","gaps":["Protease identity not molecularly defined","Functional consequence of clipped-H3 deposition for replication genes not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"Structural and biochemical characterization of the histone chaperone PfAsf1 depositing H3/H4 dimers established a molecular route for H3 assembly into nucleosomes in the parasite.","evidence":"PfAsf1 crystal structure at 2.4 Å, Co-IP/pulldown with H3/H4, in vitro disome assembly, site-directed mutagenesis","pmids":["33501928"],"confidence":"High","gaps":["In vivo requirement of PfAsf1 for H3 deposition not tested genetically","Coordination with other chaperones/replication machinery not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"Identifying PfPRMT5 as the writer of symmetric H3R2me2s (and R8) at invasion genes, with disruption 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explained"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Nucleosome (H3/H4 dimer deposited by PfAsf1) [#22]"],"partners":["PFGCN5 (ACETYLTRANSFERASE, K9/K14) [#2, #3]","PFSET7 (METHYLTRANSFERASE, K4/K9) [#18]","PFSETVS (METHYLTRANSFERASE, K36ME3) [#14]","PFPRMT5 (SYMMETRIC ARGININE DIMETHYLTRANSFERASE, R2/R8) [#24]","PFHP1 (CHROMODOMAIN READER OF H3K9ME2/3) [#10]","PF14-3-3I (READER OF H3S28PH) [#15]","PFBDP1 (BROMODOMAIN READER OF ACETYLATED H3) [#17, #23]","PFASF1 (HISTONE CHAPERONE) [#22]"],"other_free_text":["N-terminal tail proteolytically clipped at position 21 by a nuclear cathepsin C-like activity; clipped H3 enriched upstream of DNA replication/repair genes [#20]","At least two H3 family members exist (H3 and variant H3.3); this record concerns canonical H3 (PF3D7_0610400) [#1]","H3K9ac/H3K9me3 balance and H3K4me3/H3K36me3 govern activation vs silencing of var genes 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molecular cloning\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single sequencing study, no functional follow-up described in abstract\",\n      \"pmids\": [\"7723778\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Plasmodium falciparum histone H3 was cloned and expressed as a recombinant protein; sequence analysis revealed that the apicomplexan H3 proteins harbor novel and rare features compared to other eukaryotes, establishing the existence of at least two H3 variants (H3 and H3.3) in this parasite.\",\n      \"method\": \"Molecular cloning, sequence analysis, recombinant protein expression\",\n      \"journal\": \"DNA sequence : the journal of DNA sequencing and mapping\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, sequence and expression only, no functional assay described in abstract\",\n      \"pmids\": [\"14509838\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Recombinant PfGCN5 acetylates histone H3 (PF3D7_0610400) at lysine 8 and lysine 14 in vitro, establishing H3 as a substrate of PfGCN5 with site-specific modification at K8 and K14.\",\n      \"method\": \"In vitro HAT assay with recombinant PfGCN5 using free core histones as substrate, substrate-specific antibodies\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis-level specificity (antibody-confirmed sites), replicated in subsequent studies\",\n      \"pmids\": [\"15075257\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mass spectrometry of P. falciparum histones identified acetylation of lysines and methylation of lysines and arginines in the N-terminus of histone H3 (PF3D7_0610400). Recombinant PfH3 was efficiently acetylated by both recombinant and native PfGCN5 at K9 and K14, confirming H3 as a substrate despite sequence divergence from mammalian H3 N-termini. H3-K9 acetylation increased in late trophozoite and schizont stages during intraerythrocytic development.\",\n      \"method\": \"Mass spectrometry of purified histones, in vitro acetyltransferase assay with recombinant PfH3 and PfGCN5, immunoblotting with acetylation-specific antibodies at multiple time points\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry identification of PTM sites plus in vitro reconstitution with recombinant proteins, multiple orthogonal methods in single study\",\n      \"pmids\": [\"16410041\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Curcumin treatment caused specific hypoacetylation of histone H3 (PF3D7_0610400) at K9 and K14 (but not H4 at K5, K8, K12, K16) in P. falciparum, consistent with inhibition of PfGCN5 HAT activity, as confirmed by in vitro HAT inhibition assays with recombinant PfGCN5.\",\n      \"method\": \"In vitro HAT assay with recombinant PfGCN5, nuclear HAT activity assay, acetylation-specific antibodies\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro assay plus cellular confirmation with specific antibodies, single lab, two orthogonal methods\",\n      \"pmids\": [\"17145789\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PfGCN5-mediated acetylation of histone H3 (PF3D7_0610400) at K9 (H3K9ac) is enriched at putative promoter regions of active genes in a stage-specific manner during erythrocytic development; H3K9ac and H3K9me3 marks on H3 act antagonistically as epigenetic markers of active and silent genes respectively, genome-wide.\",\n      \"method\": \"ChIP-on-chip (chromatin immunoprecipitation with microarray), real-time PCR, treatment with PfGCN5 inhibitor\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-on-chip with functional validation by inhibitor treatment and stage-specific PCR, replicated in multiple subsequent studies\",\n      \"pmids\": [\"17449656\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Trimethylation and dimethylation of histone H3 lysine 4 (H3K4me3/me2) on PF3D7_0610400 peaks in the 5' upstream region of transcribed var genes and acts as a bookmarking epigenetic mark during the poised state; H3K9me3 acts antagonistically to K4 methylation to establish stable var gene silencing, while H3K9 acetylation competes with H3K9 methylation in the 5' flanking region to repress or activate var gene expression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) with modification-specific antibodies, real-time PCR across var gene regions\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal ChIP mapping of multiple H3 PTMs across gene regions with functional interpretation, replicated across labs\",\n      \"pmids\": [\"18028313\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"H3K9me3 on histone H3 (PF3D7_0610400) serves as an epigenetic mark controlling var gene transcription and antigenic variation, constituting a chromatin memory associated with mutually exclusive var gene expression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) with H3K9me3-specific antibodies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based localization of H3K9me3 at var gene loci, single lab, consistent with independent replication in companion studies\",\n      \"pmids\": [\"17209011\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Anacardic acid inhibits PfGCN5 HAT activity and induces hypoacetylation of histone H3 (PF3D7_0610400) at K9 and K14 (but not H4 at K5, K8, K12, K16), with ChIP-PCR confirming reduced H3K9 acetylation near promoters of downregulated genes, establishing H3K9/K14ac as functionally linked to active gene expression.\",\n      \"method\": \"In vitro HAT inhibition assay with recombinant PfGCN5, acetylation-specific antibodies, ChIP and real-time PCR, microarray gene expression\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution plus cellular ChIP and genome-wide transcriptomics, multiple orthogonal methods in single study\",\n      \"pmids\": [\"18487348\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Methyl marks were detected on K4, K9, and K36 of histone H3 (PF3D7_0610400) by site-specific methyl-lysine antibodies; two P. falciparum SET-domain protein domains expressed in a eukaryotic system showed histone methyltransferase activity towards H3 in vitro.\",\n      \"method\": \"Site-specific methyl-lysine antibodies, in vitro eukaryotic expression and HKMT activity assay\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro methyltransferase assay confirmed H3 as substrate, but the specific SET proteins responsible for each H3 site were not fully resolved in this study\",\n      \"pmids\": [\"18299133\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The chromodomain (CD) of PfHP1 binds specifically to di- and tri-methylated lysine 9 of histone H3 (PF3D7_0610400) but not to unmodified H3 or H3K4-methylated forms, establishing H3K9me2/3 as the recognition mark for PfHP1-mediated heterochromatin formation and var gene silencing.\",\n      \"method\": \"Recombinant protein binding assay (CD of PfHP1 vs. modified/unmodified H3 peptides), ChIP analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of binding specificity with recombinant domain plus ChIP validation in parasite, two orthogonal methods\",\n      \"pmids\": [\"19270070\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mass spectrometry analysis of P. falciparum asexual stage histones revealed a general preponderance of H3/H4 acetylation and H3K4me3 on histone H3. ChIP-on-chip profiling showed H3K4me3 and H3K9ac on H3 are broadly distributed across euchromatic genome regions in asynchronous parasites, with stage-specific patterns: in rings they are homogeneous across genes, while in schizonts they are enriched at the 5' end of active genes.\",\n      \"method\": \"Mass spectrometry, ChIP-on-chip with H3, H3K4me3, H3K9me3, H3K9ac antibodies, synchronized parasite analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — MS identification of modifications plus genome-wide ChIP-on-chip in multiple parasite stages, orthogonal methods\",\n      \"pmids\": [\"19497874\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"H3K9ac and H3K4me3 modifications on histone H3 (PF3D7_0610400) are preferentially deposited at H2A.Z-containing nucleosomes in euchromatic intergenic regions; H3K9ac at promoter regions correlates with transcriptional status dynamically throughout the intraerythrocytic cycle, while H3K4me3 shows stage-specific regulation peaking at trophozoite stage.\",\n      \"method\": \"Genome-wide ChIP with next-generation sequencing (ChIP-seq) for H2A.Z, H3K9ac, H3K4me3; RNA-seq at 8 time points; linear amplification library preparation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq with temporal RNA-seq across 8 time points, multiple marks analyzed, independently consistent with prior and subsequent studies\",\n      \"pmids\": [\"21187892\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Recombinant P. falciparum histone H3 (PfH3/PF3D7_0610400) directly stimulated production of IL-8 and other inflammatory mediators by primary human endothelial cells via Src family kinases and p38 MAPK signaling, and induced endothelial permeability through a charge-dependent mechanism; these effects were abrogated by histone-specific antibodies and by recombinant human activated protein C, which proteolytically cleaved PfH3.\",\n      \"method\": \"Recombinant PfH3 treatment of primary human dermal microvascular endothelial cells, antibody blocking, kinase inhibitors, live cell imaging, activated protein C cleavage assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — recombinant protein functional assay with multiple orthogonal validations (antibody abrogation, protease cleavage, signaling pathway inhibitors), single lab\",\n      \"pmids\": [\"22260922\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PfSETvs-dependent trimethylation of histone H3 lysine 36 (H3K36me3) on PF3D7_0610400, present along the entire var gene body including the transcription start site, is required for silencing of var genes; knockout of PfSETvs abolished H3K36me3 at var genes and resulted in transcription of virtually all var genes simultaneously.\",\n      \"method\": \"PfSETvs knockout by targeted disruption, ChIP with H3K36me3-specific antibodies, RNA-seq, flow cytometry, immunofluorescence\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with genome-wide ChIP and transcriptomics, multiple orthogonal readouts, published in high-impact journal\",\n      \"pmids\": [\"23823717\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fourteen phosphorylation sites on histone H3 (PF3D7_0610400) and other histones were detected by LC-MS/MS in P. falciparum asexual blood stages; Pf14-3-3I was identified as a phospho-H3 reader that preferentially binds H3S28ph over H3S10ph, independent of modification of neighboring residues.\",\n      \"method\": \"LC-MS/MS with phosphopeptide enrichment, recombinant Pf14-3-3I protein binding to purified parasite histones, ITC with H3 phosphopeptides, in silico structural analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS-based PTM identification plus in vitro binding assay with purified recombinant protein and ITC quantification, multiple orthogonal methods\",\n      \"pmids\": [\"23308157\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Genome-wide ChIP-on-chip mapping of twelve histone modifications including H3K9ac, H3K14ac, H3K56ac, H3K4me3, and H3K79me3 on histone H3 (PF3D7_0610400) throughout the P. falciparum IDC showed dynamic stage-specific enrichment; H3 acetylations correlate with transcript levels and show differential affinity to genomic regions. H4K8ac occupies predominantly promoter regions while H3 marks occur at 5' ends of coding sequences, with promoter occupancy of H4K8ac retained when ectopically inserted at a different locus.\",\n      \"method\": \"ChIP-on-chip with modification-specific antibodies across erythrocytic stages, ectopic locus insertion\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-on-chip for 12 histone marks with functional ectopic insertion validation, multiple orthogonal methods\",\n      \"pmids\": [\"23468622\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PfBDP1 bromodomain protein binds to acetylated histone H3 (PF3D7_0610400) at transcriptional start sites of invasion-related genes; conditional PfBDP1 knockdown reduces expression of invasion genes and impairs parasite invasion.\",\n      \"method\": \"Conditional knockdown (DiCre or similar), ChIP-seq, co-immunoprecipitation, RNA-seq\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KD with clear invasion phenotype, ChIP-seq localization, Co-IP binding to acetylated H3, multiple orthogonal methods\",\n      \"pmids\": [\"26067602\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PfSET7 is an AdoMet-dependent histone methyltransferase that methylates histone H3 (PF3D7_0610400) at K4 and K9 (with highest activity towards these residues); PfSET7 displays specific substrate preference towards nucleosomes with pre-existing H3K14 acetylation.\",\n      \"method\": \"Recombinant PfSET7 expression and purification, in vitro methyltransferase assay with H3 substrates, steady-state kinetics, substrate preference assay with H3K14ac-containing nucleosomes\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — full enzymatic characterization in vitro with recombinant enzyme, steady-state kinetics, substrate specificity defined by nucleosome modifications\",\n      \"pmids\": [\"26902486\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A crystal structure of the PfGCN5 bromodomain in complex with the PCAF bromodomain inhibitor L-45 was solved, rationalizing selective binding to PCAF/GCN5 bromodomains; PfGCN5 bromodomain interaction with histone H3.3 (a variant) was disrupted in cells by L-45, but this experiment was performed with H3.3 (the variant), not canonical H3 (PF3D7_0610400).\",\n      \"method\": \"Co-crystal structure of PfGCN5-BRD with inhibitor, nanoBRET assay in cells\",\n      \"journal\": \"Angewandte Chemie (International ed. in English)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — crystal structure is of PfGCN5 bromodomain, not H3 itself; the cellular interaction tested was with H3.3 variant not canonical H3; indirect relevance to PF3D7_0610400\",\n      \"pmids\": [\"27966810\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Proteolytic clipping of the N-terminal tail of nucleosome-associated histone H3 (PF3D7_0610400) at amino acid position 21 occurs in P. falciparum via a cathepsin C-like activity present in nuclear parasite extracts; ectopically expressed clipped H3 (PfH3p-HA) is targeted to the nucleus, integrates into mononucleosomes, and ChIP-seq shows it is highly enriched upstream of six DNA replication/repair genes, demarcating a specific 1.5 kb chromatin island.\",\n      \"method\": \"Nuclear extract proteolytic clipping assay, ectopic expression of truncated H3-HA, ChIP-seq, subcellular fractionation/localization\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical clipping activity in nuclear extracts plus functional ectopic expression with ChIP-seq genome-wide localization, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30833341\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"H3K18ac and H3K27ac modifications on histone H3 (PF3D7_0610400) dynamically mark regulatory sequences upstream of genes during the asexual life cycle, co-localizing with PfAP2-I, PfBDP1, and PfH2A.Z at stably positioned nucleosomes within exposed DNA at active transcriptional start sites; transient transfection assays showed that sequences enriched for these marks possess promoter activity in schizont stages but no enhancer-like activity.\",\n      \"method\": \"ChIP-seq for H3K18ac, H3K27ac, H3K4me1, H3K27ac; integration with existing datasets; transient transfection promoter activity assays\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with functional validation by transfection assays, multiple marks analyzed, integration with independent datasets\",\n      \"pmids\": [\"33225957\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plasmodium falciparum histone chaperone PfAsf1 specifically interacts with histone H3 (PF3D7_0610400) and H4 and deposits the H3/H4 dimer onto DNA to form disomes; critical residues of PfAsf1 involved in H3/H4 interaction were mapped by site-directed mutagenesis, and the crystal structure of PfAsf1 N-terminal domain was solved at 2.4 Å.\",\n      \"method\": \"X-ray crystallography of PfAsf1 (2.4 Å), co-immunoprecipitation/pulldown of PfAsf1 with P. falciparum H3/H4, in vitro nucleosome assembly (disome formation) assay, site-directed mutagenesis of PfAsf1\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus in vitro reconstitution of H3/H4 chaperone activity and mutagenesis of binding interface, multiple orthogonal methods\",\n      \"pmids\": [\"33501928\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The PfBDP1 bromodomain preferentially recognizes tetra-acetylated histone H4 and also weakly interacts with multi-acetylated H2A.Z in addition to previously reported acetylated histone H3 (PF3D7_0610400); a crystal structure of PfBDP1-BRD reveals a unique binding mechanism distinct from human bromodomain families.\",\n      \"method\": \"Crystal structure of PfBDP1 bromodomain, solution NMR spectroscopy, ITC binding assays with acetylated histone peptides\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure plus NMR and ITC for binding, but interaction with canonical H3 (PF3D7_0610400) was a weaker/secondary finding compared to H4 in this study\",\n      \"pmids\": [\"36328269\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PfPRMT5 catalyzes symmetric dimethylation of histone H3 (PF3D7_0610400) at R2 (H3R2me2s) and R8 in vitro; genome-wide H3R2me2s marks invasion-related genes and other loci, and PfPRMT5 disruption depletes H3R2me2s and reduces invasion efficiency and invasion gene transcription.\",\n      \"method\": \"In vitro methyltransferase assay with recombinant PfPRMT5, ChIP-seq for H3R2me2s, conditional disruption of PfPRMT5, transcriptomics, interactome (Co-IP/MS)\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of H3 methylation plus genome-wide ChIP-seq and genetic disruption with defined phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"37349497\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"P. falciparum histone H3 (PF3D7_0610400) is the canonical nucleosomal histone H3 whose N-terminal tail undergoes extensive post-translational modifications — including acetylation at K9 and K14 (written by PfGCN5), methylation at K4, K9, K36 and K79 (by distinct SET-domain methyltransferases including PfSETvs for K36me3 and PfSET7 for K4/K9), symmetric dimethylation at R2 and R8 (by PfPRMT5), phosphorylation at S10 and S28 (read by Pf14-3-3I), and proteolytic N-terminal clipping (by a cathepsin C-like nuclear activity); these marks collectively determine heterochromatin assembly at virulence and subtelomeric loci (via H3K9me3 recognized by PfHP1), activate or repress var gene expression (via H3K36me3, H3K4me3, H3K9ac/me3 balance), direct invasion gene expression (via H3K9ac/H3R2me2s recognized by PfBDP1), and regulate DNA replication gene chromatin through incorporation of clipped H3, while extracellular H3 released from lysed infected erythrocytes directly induces endothelial inflammation and permeability through Src/p38 MAPK signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0610400 is the canonical nucleosomal histone H3 of Plasmodium falciparum, first identified by sequencing as a divergent apicomplexan H3 [#0, #1], and it functions as the central substrate scaffold on which the parasite's chromatin-based gene regulation is written and read. Its N-terminal tail is subject to extensive, enzyme-specific modification: PfGCN5 acetylates K9 and K14 [#2, #3], distinct SET-domain methyltransferases including PfSET7 (K4/K9) and PfSETvs (K36me3) methylate lysine residues [#14, #18], PfPRMT5 symmetrically dimethylates R2 and R8 [#24], and the tail is phosphorylated at multiple serines [#15] and proteolytically clipped at position 21 by a nuclear cathepsin C-like activity [#20]. These marks partition the genome into functional chromatin states: H3K9ac and H3K4me3 broadly mark active euchromatin and 5' ends of transcribed genes in a stage-specific manner during intraerythrocytic development [#5, #11, #12], while H3K9me3 recruits the PfHP1 chromodomain to establish heterochromatin and enforce mutually exclusive var gene silencing and antigenic variation [#7, #10]. PfSETvs-dependent H3K36me3 across var gene bodies is required to keep var genes silent [#14], and reader proteins including PfBDP1 (acetyl-H3) and Pf14-3-3I (phospho-H3S28) couple these marks to invasion gene expression and downstream signaling [#15, #17, #24]. Clipped H3 integrates into mononucleosomes and demarcates a chromatin island upstream of DNA replication/repair genes [#20], and extracellular recombinant H3 released from infected erythrocytes directly triggers endothelial inflammation and permeability through Src-family kinase and p38 MAPK signaling [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing the primary sequence of parasite H3 was the necessary first step to define this protein as a bona fide histone H3 in P. falciparum.\",\n      \"evidence\": \"DNA sequencing/molecular cloning of the H3 gene\",\n      \"pmids\": [\"7723778\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Sequence only, no functional characterization\", \"Variant composition of the H3 family not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Recombinant expression and sequence analysis showed apicomplexan H3 has rare/novel features and revealed at least two H3 variants (H3 and H3.3), framing the question of whether the divergent tail could still serve as a modification substrate.\",\n      \"evidence\": \"Molecular cloning, sequence analysis, recombinant protein expression\",\n      \"pmids\": [\"14509838\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No enzymatic modification assays\", \"Functional distinction between H3 and H3.3 not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying PfGCN5 as the enzyme acetylating H3 at K9/K14 and mapping methyl/acetyl marks by mass spectrometry established that despite tail divergence, parasite H3 carries a conventional repertoire of PTMs deposited by defined writers.\",\n      \"evidence\": \"In vitro HAT assays with recombinant PfGCN5, mass spectrometry of purified histones, acetylation-specific antibodies, stage timepoints (builds on earlier K8/K14 assignment)\",\n      \"pmids\": [\"15075257\", \"16410041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site nomenclature (K8 vs K9) reconciliation across studies\", \"In vivo requirement of PfGCN5 for these marks not tested genetically\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Chemical inhibition of PfGCN5 (curcumin, anacardic acid) causing specific H3K9/K14 hypoacetylation with reduced expression of target genes linked H3 acetylation causally to active transcription and to antiparasitic action.\",\n      \"evidence\": \"In vitro HAT inhibition assays, acetylation-specific antibodies, ChIP-PCR, microarray transcriptomics\",\n      \"pmids\": [\"17145789\", \"18487348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibitors may have off-target effects beyond PfGCN5\", \"Direct genetic knockout of PfGCN5 not performed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genome-wide ChIP mapping established that H3K9ac marks active promoters while H3K9me3 marks silent loci, and that H3K4/K9 methylation and H3K9 acetylation act antagonistically to control var gene switching — defining H3 as the carrier of epigenetic memory for antigenic variation.\",\n      \"evidence\": \"ChIP-on-chip, ChIP-PCR with modification-specific antibodies across var loci and genome-wide, site-specific methyl-lysine antibodies with in vitro SET-domain HKMT assays\",\n      \"pmids\": [\"17449656\", \"18028313\", \"17209011\", \"18299133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific SET enzymes deposit each methyl mark not fully resolved here\", \"Mechanism enforcing mutual exclusivity not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that the PfHP1 chromodomain binds H3K9me2/3 but not unmodified or H3K4me forms identified the direct reader that translates the H3K9me mark into heterochromatin formation and var silencing.\",\n      \"evidence\": \"Recombinant PfHP1 chromodomain binding to modified H3 peptides, ChIP validation in parasites\",\n      \"pmids\": [\"19270070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors recruited by PfHP1 not defined here\", \"Structural basis of specificity not solved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"High-resolution ChIP-seq with temporal RNA-seq linked H3K9ac/H3K4me3 dynamics to H2A.Z-containing euchromatic nucleosomes and to transcriptional timing across the intraerythrocytic cycle, integrating H3 marks into genome-wide chromatin architecture.\",\n      \"evidence\": \"ChIP-seq for H2A.Z, H3K9ac, H3K4me3; RNA-seq at 8 timepoints; mass spectrometry\",\n      \"pmids\": [\"21187892\", \"19497874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causality between mark deposition and transcription not tested by perturbation\", \"Reader proteins for these euchromatic marks not identified here\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that extracellular recombinant PfH3 activates endothelial inflammation and permeability via Src/p38 MAPK signaling revealed a non-chromatin, pathogenic role for H3 released from lysed infected cells in malaria pathology.\",\n      \"evidence\": \"Recombinant PfH3 treatment of endothelial cells, antibody blocking, kinase inhibitors, live imaging, activated protein C cleavage\",\n      \"pmids\": [\"22260922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endothelial receptor for extracellular H3 not identified\", \"In vivo contribution to malaria pathology not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"PfSETvs knockout abolishing H3K36me3 and de-repressing all var genes simultaneously established H3K36me3 as a required silencing mark and defined the enzyme responsible, advancing the mechanism of mutually exclusive var expression.\",\n      \"evidence\": \"Targeted PfSETvs knockout, ChIP with H3K36me3 antibodies, RNA-seq, flow cytometry, immunofluorescence\",\n      \"pmids\": [\"23823717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H3K36me3 mechanistically silences var bodies not defined\", \"Reader of H3K36me3 not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Detection of 14 histone phosphosites and identification of Pf14-3-3I as a phospho-H3S28 reader, plus genome-wide mapping of twelve H3 acetyl/methyl marks, expanded the H3 PTM landscape and its stage-specific genomic distribution.\",\n      \"evidence\": \"LC-MS/MS phosphoproteomics, recombinant Pf14-3-3I binding and ITC, ChIP-on-chip for twelve marks, ectopic locus insertion\",\n      \"pmids\": [\"23308157\", \"23468622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinases depositing H3S10/S28ph not identified\", \"Functional consequence of Pf14-3-3I binding not tested by perturbation\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"PfBDP1 binding to acetylated H3 at invasion gene start sites, with knockdown impairing invasion, connected H3 acetylation reading to the invasion transcriptional program and a defined biological phenotype.\",\n      \"evidence\": \"Conditional PfBDP1 knockdown, ChIP-seq, Co-IP, RNA-seq\",\n      \"pmids\": [\"26067602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise acetyl-H3 residues bound not fully mapped here\", \"Whether PfBDP1 also reads other histones not addressed here\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Enzymatic characterization of PfSET7 as an H3K4/K9 methyltransferase with preference for pre-existing H3K14ac established cross-talk between acetylation and methylation writing on the same H3 tail.\",\n      \"evidence\": \"Recombinant PfSET7 in vitro methyltransferase assays, steady-state kinetics, nucleosome substrate preference\",\n      \"pmids\": [\"26902486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo genomic targets of PfSET7 not mapped here\", \"Relative contribution of PfSET7 vs other SET enzymes to K4/K9me not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery of cathepsin C-like N-terminal clipping of H3 at position 21 and mapping of clipped H3 to a chromatin island upstream of DNA replication/repair genes revealed a proteolytic modification mechanism distinct from side-chain PTMs.\",\n      \"evidence\": \"Nuclear extract clipping assay, ectopic expression of truncated H3-HA, ChIP-seq, subcellular fractionation\",\n      \"pmids\": [\"30833341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease identity not molecularly defined\", \"Functional consequence of clipped-H3 deposition for replication genes not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural and biochemical characterization of the histone chaperone PfAsf1 depositing H3/H4 dimers established a molecular route for H3 assembly into nucleosomes in the parasite.\",\n      \"evidence\": \"PfAsf1 crystal structure at 2.4 Å, Co-IP/pulldown with H3/H4, in vitro disome assembly, site-directed mutagenesis\",\n      \"pmids\": [\"33501928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement of PfAsf1 for H3 deposition not tested genetically\", \"Coordination with other chaperones/replication machinery not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying PfPRMT5 as the writer of symmetric H3R2me2s (and R8) at invasion genes, with disruption reducing invasion, added arginine methylation to the H3 code governing the invasion program.\",\n      \"evidence\": \"In vitro PfPRMT5 methyltransferase assay, ChIP-seq for H3R2me2s, conditional PfPRMT5 disruption, transcriptomics, interactome\",\n      \"pmids\": [\"37349497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reader of H3R2me2s not defined\", \"Interplay of H3R2me2s with adjacent H3K4 marks not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many H3 writers, readers, and clipping activities are coordinated in vivo to switch a single var gene on while silencing the rest, and the identities of the H3-clipping protease and several implicated kinases, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular identity of the H3-clipping cathepsin C-like protease unknown\", \"Kinases for H3S10/S28ph not identified\", \"Mechanism enforcing mutually exclusive var expression from H3 marks not fully explained\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0046982\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0031492\", \"supporting_discovery_ids\": [20, 22]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2, 3, 10, 15, 17, 18, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000786\", \"supporting_discovery_ids\": [11, 12, 20, 22]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0000792\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"GO:0005615\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006325\", \"supporting_discovery_ids\": [11, 12, 16]},\n      {\"term_id\": \"GO:0006338\", \"supporting_discovery_ids\": [20, 22]},\n      {\"term_id\": \"GO:0140718\", \"supporting_discovery_ids\": [10, 14, 7]},\n      {\"term_id\": \"GO:0045814\", \"supporting_discovery_ids\": [7, 14]},\n      {\"term_id\": \"GO:0006355\", \"supporting_discovery_ids\": [5, 6, 17, 24]},\n      {\"term_id\": \"GO:0006954\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\n      \"Nucleosome (H3/H4 dimer deposited by PfAsf1) [#22]\"\n    ],\n    \"partners\": [\n      \"PfGCN5 (acetyltransferase, K9/K14) [#2, #3]\",\n      \"PfSET7 (methyltransferase, K4/K9) [#18]\",\n      \"PfSETvs (methyltransferase, K36me3) [#14]\",\n      \"PfPRMT5 (symmetric arginine dimethyltransferase, R2/R8) [#24]\",\n      \"PfHP1 (chromodomain reader of H3K9me2/3) [#10]\",\n      \"Pf14-3-3I (reader of H3S28ph) [#15]\",\n      \"PfBDP1 (bromodomain reader of acetylated H3) [#17, #23]\",\n      \"PfAsf1 (histone chaperone) [#22]\"\n    ],\n    \"other_free_text\": [\n      \"N-terminal tail proteolytically clipped at position 21 by a nuclear cathepsin C-like activity; clipped H3 enriched upstream of DNA replication/repair genes [#20]\",\n      \"At least two H3 family members exist (H3 and variant H3.3); this record concerns canonical H3 (PF3D7_0610400) [#1]\",\n      \"H3K9ac/H3K9me3 balance and H3K4me3/H3K36me3 govern activation vs silencing of var genes and antigenic variation [#5, #6, #7, #14]\",\n      \"Extracellular recombinant PfH3 induces endothelial inflammation and permeability via Src/p38 MAPK and is cleaved by activated protein C [#13]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0610400","name":null,"product":"histone H3","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0108800","name":null,"product":"histone H3, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1139900","name":null,"product":"histone H3, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"H3","evaluation":null}