{"gene":"PF3D7_1451400","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2009,"finding":"Sir2B (PF3D7_1451400) is an NAD+-dependent histone deacetylase required for silencing of specific var gene subsets classified by their conserved promoter type; in parasites lacking Sir2B, mutually exclusive expression of var genes breaks down, and Sir2B is involved in cis spreading of silenced chromatin into adjacent regions from the var promoter.","method":"Genetic disruption (knockout) of Sir2B in P. falciparum with var gene expression analysis and chromatin-based assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined molecular phenotype (loss of mutual exclusion, derepression of specific var subsets, chromatin spreading defect), replicated across multiple independent clones and consistent with parallel Sir2A characterization in the same study","pmids":["19402747"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"Parasites lacking Sir2B (PF3D7_1451400) do not show the elongated telomeric repeats seen in Sir2A knockouts, demonstrating that Sir2B, unlike Sir2A, is not required for telomeric end protection.","method":"Genetic disruption (knockout) of Sir2B with telomere-length analysis","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct negative finding from a clean knockout, single lab, reported as a comparative result within the same study","pmids":["19402747"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"finding":"In mature Sir2B knockout parasites, PfH2A.Z is lost from the transcription start site of de-repressed var genes, indicating that Sir2B (PF3D7_1451400) normally promotes or maintains H2A.Z occupancy at active var promoters during the intraerythrocytic life cycle, a mechanism distinct from Sir2A which antagonizes H2A.Z occupancy.","method":"Chromatin immunoprecipitation (ChIP) of PfH2A.Z in Sir2B knockout versus wild-type parasites across lifecycle stages","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP in genetically defined knockout line, single lab, two orthogonal methods (ChIP + transcriptional analysis), contrasting Sir2A and Sir2B phenotypes","pmids":["21379342"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"Genetic disruption of Sir2B (PF3D7_1451400) in NF54 and FCR-3 P. falciparum strains caused no dramatic changes in var gene expression, contrasting with previously reported effects in 3D7, demonstrating that Sir2B's role in var gene regulation is dependent on parasite genetic background.","method":"Genetic disruption of Sir2B in multiple P. falciparum strains (3D7, NF54, FCR-3) with quantitative var gene expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockouts in three independent strains with qPCR-based var expression readout, single lab but multiple strains providing comparative context","pmids":["25780929"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"NF54"},{"species":"Plasmodium falciparum","strain":"FCR-3"}]},{"year":2021,"finding":"Sir2B (PF3D7_1451400) transcription is downregulated at the mid-ring stage in response to febrile temperature; PfHsp90 acts as a repressor of Sir2B transcription by occupying Sir2B promoter-proximal regions and recruiting H3K9me3 to confer a heterochromatic state, and this repression is reversed by Hsp90 inhibitors (17-AAG or Radicicol). Reduced Sir2B occupancy at sub-telomeric var promoters correlates with de-repression of var genes.","method":"ChIP of PfHsp90 and H3K9me3 at Sir2B promoter; qPCR of Sir2B transcription after heat treatment and Hsp90 inhibitor treatment; ChIP of PfSir2 at var promoters","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, pharmacological inhibition, qPCR), single lab, clear cause-and-effect relationship between Hsp90 occupancy and Sir2B repression","pmids":["33538363"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2022,"finding":"Heat shock (40°C, 2–6 h) increases Sir2B (PF3D7_1451400) transcript levels in trophozoite stages but not in ring stages, whereas exposure to elevated lactate does not alter Sir2B expression.","method":"qPCR of Sir2B transcripts in synchronised P. falciparum cultures after heat shock or lactate treatment","journal":"Molecular and biochemical parasitology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (qPCR), no mechanistic follow-up on how the transcript change affects Sir2B protein function","pmids":["35031386"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"Sir2B (PF3D7_1451400) is an NAD+-dependent histone deacetylase that silences specific subsets of var virulence genes (defined by promoter type) in P. falciparum by promoting cis spreading of heterochromatin from var promoters and maintaining H2A.Z occupancy at active var promoters; its expression is transcriptionally repressed by PfHsp90-mediated H3K9me3 deposition in response to febrile temperature, and its activity is dispensable for telomere-length regulation, with its contribution to var silencing being strain-background dependent."},"narrative":{"mechanistic_narrative":"Sir2B (PF3D7_1451400) is an NAD+-dependent histone deacetylase that silences specific subsets of var virulence genes in Plasmodium falciparum, contributing to the mutually exclusive expression that underlies antigenic variation [PMID:19402747]. Sir2B silences var subsets defined by their conserved promoter type, and its disruption breaks down mutual exclusion and derepresses these subsets by disrupting the cis spreading of silenced chromatin outward from the var promoter [PMID:19402747]. Functionally, Sir2B is distinguished from its family counterpart Sir2A on two counts: it is dispensable for telomere-length regulation, since Sir2B knockouts lack the elongated telomeric repeats seen in Sir2A knockouts [PMID:19402747], and rather than antagonizing H2A.Z it promotes or maintains PfH2A.Z occupancy at active var promoter transcription start sites, which is lost upon Sir2B disruption [PMID:21379342]. Sir2B expression is itself repressed at the transcriptional level: PfHsp90 occupies Sir2B promoter-proximal regions and recruits H3K9me3 to impose a heterochromatic state in response to febrile temperature, and reduced Sir2B occupancy at sub-telomeric var promoters correlates with var derepression [PMID:33538363]. Its contribution to var regulation is strain-background dependent, with disruption in NF54 and FCR-3 producing no dramatic var expression changes unlike in 3D7 [PMID:25780929].","teleology":[{"year":2009,"claim":"Establishing whether a second sirtuin beyond Sir2A participates in var silencing, this work showed Sir2B is an NAD+-dependent deacetylase required for silencing specific promoter-defined var subsets and for cis heterochromatin spreading from var promoters.","evidence":"Knockout of Sir2B in P. falciparum with var expression and chromatin assays","pmids":["19402747"],"confidence":"High","gaps":["Direct enzymatic activity and substrate acetyl-lysine targets not defined in this entry","Molecular basis of promoter-type selectivity unresolved","Mechanism of chromatin spreading not defined at protein-recruitment level"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"claim":"To test whether Sir2B shares Sir2A's telomeric role, telomere-length analysis of the knockout showed no repeat elongation, functionally separating Sir2B from telomere end protection.","evidence":"Telomere-length analysis of Sir2B knockout P. falciparum","pmids":["19402747"],"confidence":"Medium","gaps":["Negative finding does not exclude subtle or context-dependent telomeric contributions","Single lab, single comparative readout"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"claim":"Addressing how Sir2B acts on active promoters, ChIP showed Sir2B is needed to maintain PfH2A.Z at active var transcription start sites, defining a mechanism opposite to Sir2A's antagonism of H2A.Z.","evidence":"ChIP of PfH2A.Z in Sir2B knockout versus wild-type across lifecycle stages","pmids":["21379342"],"confidence":"Medium","gaps":["Whether Sir2B acts directly on H2A.Z deposition or indirectly is unresolved","Single lab study"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"Testing reproducibility of Sir2B's var role across genetic backgrounds, knockouts in NF54 and FCR-3 produced no dramatic var changes, establishing that Sir2B's regulatory contribution is strain-background dependent.","evidence":"Sir2B disruption in 3D7, NF54, and FCR-3 with qPCR var expression readout","pmids":["25780929"],"confidence":"Medium","gaps":["Genetic determinants underlying strain-dependence not identified","qPCR readout may miss single-locus or chromatin-level effects"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"NF54"},{"species":"Plasmodium falciparum","strain":"FCR-3"}]},{"year":2021,"claim":"Addressing how environmental stress feeds into var control, this work showed PfHsp90 represses Sir2B transcription by occupying its promoter and recruiting H3K9me3 under febrile temperature, linking heat stress to Sir2B downregulation and var derepression.","evidence":"ChIP of PfHsp90 and H3K9me3 at Sir2B promoter, qPCR after heat and Hsp90-inhibitor treatment, ChIP of PfSir2 at var promoters","pmids":["33538363"],"confidence":"Medium","gaps":["How reduced Sir2B protein quantitatively translates to specific var switching is not resolved","Direct versus indirect Hsp90-Sir2B promoter contact not distinguished"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2022,"claim":"Probing stage-specificity of Sir2B stress responsiveness, heat shock raised Sir2B transcript in trophozoites but not rings, and lactate had no effect, refining when Sir2B expression responds to thermal stress.","evidence":"qPCR of Sir2B transcripts after heat shock or lactate in synchronised cultures","pmids":["35031386"],"confidence":"Low","gaps":["Single method (qPCR) with no follow-up on protein-level or functional consequence","Apparent stage-directionality contrasts with earlier mid-ring downregulation and is not reconciled"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"It remains unknown how Sir2B enzymatic deacetylation is mechanistically coupled to promoter-type-selective var silencing, and what molecular basis underlies its strain-dependent contribution.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct substrate or interaction partner for Sir2B defined in the corpus","Structural basis of promoter-type selectivity unresolved","Genetic drivers of strain-background dependence not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFH2A.Z (OCCUPANCY MAINTAINED AT ACTIVE VAR PROMOTERS BY SIR2B) [#2]","PFHSP90 (REPRESSES SIR2B TRANSCRIPTION VIA H3K9ME3) [#4]"],"other_free_text":["Silences specific var subsets defined by conserved promoter type and promotes cis spreading of heterochromatin from var promoters [#0].","Dispensable for telomere-length regulation, unlike Sir2A [#1].","Contribution to var regulation is strain-background dependent (3D7 versus NF54/FCR-3) [#3].","Transcription is heat/febrile-temperature responsive and repressed by PfHsp90-recruited H3K9me3 [#4, #5]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"19402747","id":"PMC_19402747","title":"Sir2 paralogues cooperate to regulate virulence genes and antigenic variation in Plasmodium falciparum.","date":"2009","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/19402747","citation_count":199,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfSir2B","PfSir2b"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21379342","id":"PMC_21379342","title":"Expression of P. falciparum var genes involves exchange of the histone variant H2A.Z at the promoter.","date":"2011","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/21379342","citation_count":87,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["Sir2B","Sir2b"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18525026","id":"PMC_18525026","title":"Differential association of Orc1 and Sir2 proteins to telomeric domains in Plasmodium falciparum.","date":"2008","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/18525026","citation_count":64,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23443558","id":"PMC_23443558","title":"Sir2a regulates rDNA transcription and multiplication rate in the human malaria parasite Plasmodium falciparum.","date":"2013","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/23443558","citation_count":55,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25780929","id":"PMC_25780929","title":"Functional analysis of sirtuin genes in multiple Plasmodium falciparum strains.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25780929","citation_count":34,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfSir2B","PfSir2b"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"19666023","id":"PMC_19666023","title":"The effect of Plasmodium falciparum Sir2a histone deacetylase on clonal and longitudinal variation in expression of the var family of virulence genes.","date":"2009","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/19666023","citation_count":23,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33538363","id":"PMC_33538363","title":"Febrile temperature causes transcriptional downregulation of Plasmodium falciparum Sirtuins through Hsp90-dependent epigenetic modification.","date":"2021","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33538363","citation_count":10,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfSir2B","PfSir2b"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35031386","id":"PMC_35031386","title":"Alteration of the expression of sirtuins and var genes by heat shock in the malaria parasite Plasmodium falciparum.","date":"2022","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/35031386","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["Sir2B","Sir2b","PfSir2B","PfSir2b"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37608862","id":"PMC_37608862","title":"Molecular characterization and in silico evaluation of surfactins produced by endophytic bacteria from Phanera splendens.","date":"2023","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37608862","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfSir2B","PfSir2b"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7554,"output_tokens":1824,"usd":0.025011,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6984,"output_tokens":3004,"usd":0.05501,"stage2_stop_reason":"end_turn"},"total_usd":0.080021,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"Sir2B (PF3D7_1451400) is an NAD+-dependent histone deacetylase required for silencing of specific var gene subsets classified by their conserved promoter type; in parasites lacking Sir2B, mutually exclusive expression of var genes breaks down, and Sir2B is involved in cis spreading of silenced chromatin into adjacent regions from the var promoter.\",\n      \"method\": \"Genetic disruption (knockout) of Sir2B in P. falciparum with var gene expression analysis and chromatin-based assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined molecular phenotype (loss of mutual exclusion, derepression of specific var subsets, chromatin spreading defect), replicated across multiple independent clones and consistent with parallel Sir2A characterization in the same study\",\n      \"pmids\": [\"19402747\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Parasites lacking Sir2B (PF3D7_1451400) do not show the elongated telomeric repeats seen in Sir2A knockouts, demonstrating that Sir2B, unlike Sir2A, is not required for telomeric end protection.\",\n      \"method\": \"Genetic disruption (knockout) of Sir2B with telomere-length analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct negative finding from a clean knockout, single lab, reported as a comparative result within the same study\",\n      \"pmids\": [\"19402747\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In mature Sir2B knockout parasites, PfH2A.Z is lost from the transcription start site of de-repressed var genes, indicating that Sir2B (PF3D7_1451400) normally promotes or maintains H2A.Z occupancy at active var promoters during the intraerythrocytic life cycle, a mechanism distinct from Sir2A which antagonizes H2A.Z occupancy.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of PfH2A.Z in Sir2B knockout versus wild-type parasites across lifecycle stages\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in genetically defined knockout line, single lab, two orthogonal methods (ChIP + transcriptional analysis), contrasting Sir2A and Sir2B phenotypes\",\n      \"pmids\": [\"21379342\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Genetic disruption of Sir2B (PF3D7_1451400) in NF54 and FCR-3 P. falciparum strains caused no dramatic changes in var gene expression, contrasting with previously reported effects in 3D7, demonstrating that Sir2B's role in var gene regulation is dependent on parasite genetic background.\",\n      \"method\": \"Genetic disruption of Sir2B in multiple P. falciparum strains (3D7, NF54, FCR-3) with quantitative var gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockouts in three independent strains with qPCR-based var expression readout, single lab but multiple strains providing comparative context\",\n      \"pmids\": [\"25780929\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"NF54\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"FCR-3\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sir2B (PF3D7_1451400) transcription is downregulated at the mid-ring stage in response to febrile temperature; PfHsp90 acts as a repressor of Sir2B transcription by occupying Sir2B promoter-proximal regions and recruiting H3K9me3 to confer a heterochromatic state, and this repression is reversed by Hsp90 inhibitors (17-AAG or Radicicol). Reduced Sir2B occupancy at sub-telomeric var promoters correlates with de-repression of var genes.\",\n      \"method\": \"ChIP of PfHsp90 and H3K9me3 at Sir2B promoter; qPCR of Sir2B transcription after heat treatment and Hsp90 inhibitor treatment; ChIP of PfSir2 at var promoters\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, pharmacological inhibition, qPCR), single lab, clear cause-and-effect relationship between Hsp90 occupancy and Sir2B repression\",\n      \"pmids\": [\"33538363\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Heat shock (40°C, 2–6 h) increases Sir2B (PF3D7_1451400) transcript levels in trophozoite stages but not in ring stages, whereas exposure to elevated lactate does not alter Sir2B expression.\",\n      \"method\": \"qPCR of Sir2B transcripts in synchronised P. falciparum cultures after heat shock or lactate treatment\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (qPCR), no mechanistic follow-up on how the transcript change affects Sir2B protein function\",\n      \"pmids\": [\"35031386\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"Sir2B (PF3D7_1451400) is an NAD+-dependent histone deacetylase that silences specific subsets of var virulence genes (defined by promoter type) in P. falciparum by promoting cis spreading of heterochromatin from var promoters and maintaining H2A.Z occupancy at active var promoters; its expression is transcriptionally repressed by PfHsp90-mediated H3K9me3 deposition in response to febrile temperature, and its activity is dispensable for telomere-length regulation, with its contribution to var silencing being strain-background dependent.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Sir2B (PF3D7_1451400) is an NAD+-dependent histone deacetylase that silences specific subsets of var virulence genes in Plasmodium falciparum, contributing to the mutually exclusive expression that underlies antigenic variation [#0]. Sir2B silences var subsets defined by their conserved promoter type, and its disruption breaks down mutual exclusion and derepresses these subsets by disrupting the cis spreading of silenced chromatin outward from the var promoter [#0]. Functionally, Sir2B is distinguished from its family counterpart Sir2A on two counts: it is dispensable for telomere-length regulation, since Sir2B knockouts lack the elongated telomeric repeats seen in Sir2A knockouts [#1], and rather than antagonizing H2A.Z it promotes or maintains PfH2A.Z occupancy at active var promoter transcription start sites, which is lost upon Sir2B disruption [#2]. Sir2B expression is itself repressed at the transcriptional level: PfHsp90 occupies Sir2B promoter-proximal regions and recruits H3K9me3 to impose a heterochromatic state in response to febrile temperature, and reduced Sir2B occupancy at sub-telomeric var promoters correlates with var derepression [#4]. Its contribution to var regulation is strain-background dependent, with disruption in NF54 and FCR-3 producing no dramatic var expression changes unlike in 3D7 [#3].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing whether a second sirtuin beyond Sir2A participates in var silencing, this work showed Sir2B is an NAD+-dependent deacetylase required for silencing specific promoter-defined var subsets and for cis heterochromatin spreading from var promoters.\",\n      \"evidence\": \"Knockout of Sir2B in P. falciparum with var expression and chromatin assays\",\n      \"pmids\": [\"19402747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct enzymatic activity and substrate acetyl-lysine targets not defined in this entry\",\n        \"Molecular basis of promoter-type selectivity unresolved\",\n        \"Mechanism of chromatin spreading not defined at protein-recruitment level\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"To test whether Sir2B shares Sir2A's telomeric role, telomere-length analysis of the knockout showed no repeat elongation, functionally separating Sir2B from telomere end protection.\",\n      \"evidence\": \"Telomere-length analysis of Sir2B knockout P. falciparum\",\n      \"pmids\": [\"19402747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Negative finding does not exclude subtle or context-dependent telomeric contributions\",\n        \"Single lab, single comparative readout\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Addressing how Sir2B acts on active promoters, ChIP showed Sir2B is needed to maintain PfH2A.Z at active var transcription start sites, defining a mechanism opposite to Sir2A's antagonism of H2A.Z.\",\n      \"evidence\": \"ChIP of PfH2A.Z in Sir2B knockout versus wild-type across lifecycle stages\",\n      \"pmids\": [\"21379342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Sir2B acts directly on H2A.Z deposition or indirectly is unresolved\",\n        \"Single lab study\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Testing reproducibility of Sir2B's var role across genetic backgrounds, knockouts in NF54 and FCR-3 produced no dramatic var changes, establishing that Sir2B's regulatory contribution is strain-background dependent.\",\n      \"evidence\": \"Sir2B disruption in 3D7, NF54, and FCR-3 with qPCR var expression readout\",\n      \"pmids\": [\"25780929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Genetic determinants underlying strain-dependence not identified\",\n        \"qPCR readout may miss single-locus or chromatin-level effects\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"NF54\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"FCR-3\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Addressing how environmental stress feeds into var control, this work showed PfHsp90 represses Sir2B transcription by occupying its promoter and recruiting H3K9me3 under febrile temperature, linking heat stress to Sir2B downregulation and var derepression.\",\n      \"evidence\": \"ChIP of PfHsp90 and H3K9me3 at Sir2B promoter, qPCR after heat and Hsp90-inhibitor treatment, ChIP of PfSir2 at var promoters\",\n      \"pmids\": [\"33538363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How reduced Sir2B protein quantitatively translates to specific var switching is not resolved\",\n        \"Direct versus indirect Hsp90-Sir2B promoter contact not distinguished\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Probing stage-specificity of Sir2B stress responsiveness, heat shock raised Sir2B transcript in trophozoites but not rings, and lactate had no effect, refining when Sir2B expression responds to thermal stress.\",\n      \"evidence\": \"qPCR of Sir2B transcripts after heat shock or lactate in synchronised cultures\",\n      \"pmids\": [\"35031386\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single method (qPCR) with no follow-up on protein-level or functional consequence\",\n        \"Apparent stage-directionality contrasts with earlier mid-ring downregulation and is not reconciled\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how Sir2B enzymatic deacetylation is mechanistically coupled to promoter-type-selective var silencing, and what molecular basis underlies its strain-dependent contribution.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct substrate or interaction partner for Sir2B defined in the corpus\",\n        \"Structural basis of promoter-type selectivity unresolved\",\n        \"Genetic drivers of strain-background dependence not identified\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0017136\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0004407\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000792\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006342\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0045892\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfH2A.Z (occupancy maintained at active var promoters by Sir2B) [#2]\",\n      \"PfHsp90 (represses Sir2B transcription via H3K9me3) [#4]\"\n    ],\n    \"other_free_text\": [\n      \"Silences specific var subsets defined by conserved promoter type and promotes cis spreading of heterochromatin from var promoters [#0].\",\n      \"Dispensable for telomere-length regulation, unlike Sir2A [#1].\",\n      \"Contribution to var regulation is strain-background dependent (3D7 versus NF54/FCR-3) [#3].\",\n      \"Transcription is heat/febrile-temperature responsive and repressed by PfHsp90-recruited H3K9me3 [#4, #5].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1451400","name":null,"product":"transcriptional regulatory protein sir2b","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1315100","name":null,"product":"transcriptional regulatory protein sir2b","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1230700","name":null,"product":"transcriptional regulatory protein sir2b, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"Sir2B","evaluation":null}