{"gene":"ZBTB46","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2012,"finding":"Zbtb46 is selectively expressed by classical DCs (cDCs) and committed cDC progenitors (pre-cDCs) but not by plasmacytoid DCs, monocytes, macrophages, or other immune lineages. Overexpression of Zbtb46 in bone marrow progenitors inhibited granulocyte potential and promoted cDC development. Zbtb46-deficient cDCs maintained expression of G-CSF and LIF receptors that are normally downregulated in cDCs, indicating Zbtb46 enforces cDC identity by restricting responsiveness to non-DC growth factors.","method":"Homologous recombination (GFP knockin), bone marrow progenitor overexpression, Zbtb46-deficient mouse analysis, flow cytometry, developmental potential assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function and gain-of-function with specific cellular phenotypic readouts, replicated across two independent papers in the same issue","pmids":["22615127"],"is_preprint":false},{"year":2012,"finding":"zDC (Zbtb46/Btbd4) is specifically expressed by cDCs and committed cDC precursors but not monocytes, pDCs, or other immune cells. A DTR knockin at the zDC locus allows selective depletion of cDCs upon diphtheria toxin injection, sparing pDCs, monocytes, macrophages, and NK cells.","method":"DTR cDNA knockin into zDC locus, diphtheria toxin depletion, flow cytometry, bone marrow chimeras, immune challenge models (T. gondii, melanoma)","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockin with functional depletion validated in vivo, replicated in independent lab concurrent with PMID:22615127","pmids":["22615130"],"is_preprint":false},{"year":2017,"finding":"ZBTB46 is negatively regulated by androgen receptor (AR) signaling via miR-1-mediated downregulation in prostate cancer cells. ZBTB46 transcriptionally regulates SNAI1, a key EMT driver, thereby promoting epithelial-to-mesenchymal transition and metastasis after androgen deprivation.","method":"miRNA overexpression/knockdown, ZBTB46 overexpression/knockdown, transcriptional reporter assays, cell migration/invasion assays, in vivo tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional loss/gain-of-function with defined downstream target (SNAI1), single lab with multiple methods","pmids":["28692046"],"is_preprint":false},{"year":2018,"finding":"ZBTB46 acts as a transcriptional coactivator that binds to the promoter of PTGS1 (prostaglandin-endoperoxide synthase 1) and transcriptionally upregulates PTGS1 levels. ZBTB46 is regulated upstream by the androgen-responsive gene SPDEF, placing it in the AR-SPDEF-ZBTB46-PTGS1 axis during neuroendocrine prostate cancer differentiation.","method":"ChIP assay (ZBTB46 binding to PTGS1 promoter), ZBTB46 overexpression/knockdown, luciferase reporter, in vitro and in vivo tumor models, PTGS1 inhibitor sensitivity assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus functional overexpression/knockdown, single lab","pmids":["30312731"],"is_preprint":false},{"year":2019,"finding":"ZBTB46 transcriptionally activates LIF expression in prostate cancer cells by physically interacting with the regulatory sequence of the LIF gene. High ZBTB46 output activates LIF-STAT3 signaling, promoting neuroendocrine differentiation. ZBTB46 is induced by androgen deprivation therapy and is upregulated in high-grade prostate tumors.","method":"ChIP assay (ZBTB46 binding to LIF regulatory sequence), ZBTB46 overexpression/knockdown, LIF-STAT3 signaling assays, IHC on patient samples, serum LIF measurement","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct binding to LIF regulatory sequence plus downstream signaling validation, single lab","pmids":["30962287"],"is_preprint":false},{"year":2022,"finding":"ZBTB46 restrains the inflammatory properties of ILC3s in the intestine, including OX40L-dependent expansion of Th17 cells. ZBTB46 expression in CCR6+ ILC3s is imprinted by RORγt, fine-tuned by microbiota-derived signals, and increased by pro-inflammatory cytokines. ZBTB46+ ILC3s are a major source of IL-22, and their selective depletion renders mice susceptible to enteric infection.","method":"Single-cell transcriptomics, conditional cell depletion (DTR-based), genetic loss-of-function, T cell co-culture assays, intestinal infection models (enteric infection), IL-22 measurement","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including scRNA-seq, genetic depletion, and in vivo infection models with defined phenotypic readouts, published in Nature","pmids":["35831503"],"is_preprint":false},{"year":2022,"finding":"In zebrafish, Zbtb46 binds to a 5'-TGACGT-3' motif in the promoters of cd80/86 and cd40 genes in resting dendritic cells, where it establishes a repressive histone modification pattern (H3K4me0/H3K9me3/H3K27me3) by organizing NuRD (Mdb3/NuRD) and Hdac3/NCoR corepressor complexes through recruitment of Hdac1/2 and Hdac3. Upon TLR9 signaling, E3 ubiquitin ligase Cullin1/Fbxw11 mediates Zbtb46 degradation, releasing promoters for epigenetic reprogramming to an activated state (H3K4me3/H3K9ac/H3K27ac) and enabling CD80/86 and CD40 expression.","method":"ChIP-qPCR, mass spectrometry, Zbtb46 knockout zebrafish (CRISPR), co-immunoprecipitation, flow cytometry, T cell activation assays, TLR9 pathway analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP-qPCR identifying binding motif, mass spectrometry identifying corepressor complexes, genetic KO with defined phenotype, multiple orthogonal methods in single study","pmids":["35675955"],"is_preprint":false},{"year":2022,"finding":"During DC development from bone marrow precursors, cDC-primed cells within Ly6DhiZbtb46- precursors rapidly upregulate Zbtb46 and pass through a Zbtb46+Ly6D+ intermediate stage before acquiring cDC phenotype after cell division. Type I IFN arrests cDC-primed cells at the Zbtb46+Ly6D+ stage, limiting cDC output and promoting pDC output.","method":"Single-cell transcriptomics, high-dimensional flow cytometry, cell fate analysis (in vitro and in vivo), cytokine stimulation experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — single-cell transcriptomics combined with cell fate tracking in vitro and in vivo, multiple orthogonal methods","pmids":["35705536"],"is_preprint":false},{"year":2024,"finding":"ZBTB46 controls tumor angiogenesis and anti-tumor immunity. In endothelial cells, Zbtb46 deficiency leads to a highly angiogenic phenotype (dysfunctional vasculature). In bone marrow progenitors, Zbtb46 deficiency upregulates Cebpb, diverting DC differentiation toward immunosuppressive myeloid lineage output. Enforced Zbtb46 expression normalizes tumor vessels and, by suppressing Cebpb, skews progenitors toward immunostimulatory myeloid output. Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy.","method":"Endothelial cell-specific and bone marrow-specific Zbtb46 knockout/overexpression, in vivo tumor models, transcriptomic analysis, Cebpb epistasis analysis, vascular normalization assays, anti-PD1 combination therapy","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic gain- and loss-of-function with mechanistic pathway identification (Cebpb), in vivo tumor models, published in Nature Immunology","pmids":["39134750"],"is_preprint":false},{"year":2020,"finding":"Radiation-induced apoptotic bodies activate STAT5/Zbtb46 signaling in bone marrow progenitors, increasing Zbtb46 expression and enhancing subsequent DC immune-activating potential. Depletion of apoptotic bodies using annexin beads reversed these effects, confirming the apoptotic body → STAT5 → Zbtb46 pathway.","method":"In vitro irradiation of bone marrow progenitors, DC differentiation, apoptotic body depletion (annexin beads), flow cytometry, ELISA, adaptive dose experiments in vivo","journal":"International journal of radiation biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic/pharmacologic pathway dissection with annexin bead depletion validating the mechanism, single lab, single study","pmids":["32396024"],"is_preprint":false},{"year":2021,"finding":"PCK1 (phosphoenolpyruvate carboxykinase 1) is regulated by the ZBTB46 transcription factor upon activation of LIF signaling. ChIP analysis confirmed ZBTB46 binding at PCK1 regulatory regions. Upregulation of PCK1 reciprocally increases ZBTB46 levels, forming a positive feedback loop that promotes neuroendocrine differentiation in CRPC.","method":"RNA-seq, ChIP analysis (ZBTB46 binding to PCK1), in vitro cell lines, in vivo animal models, PCK1 inhibitor treatment","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct ZBTB46 binding plus in vitro and in vivo functional validation, single lab","pmids":["34815524"],"is_preprint":false},{"year":2021,"finding":"Forced expression of Zbtb46 in ESC-derived progenitors suppresses myeloid development (reduced CD11b+ cells, lower Irf8 and myeloid gene expression), interferes with mesoderm formation, and inhibits cell proliferation, while promoting erythroid colony formation and increasing adult hemoglobin (Hbb-b1) expression and CD105+ endothelial-like cell formation.","method":"Chemically inducible Zbtb46 overexpression in mouse ESC lines, flow cytometry, gene expression profiling, colony assays","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with multiple lineage readouts and transcriptomic profiling, single lab","pmids":["34058047"],"is_preprint":false},{"year":2025,"finding":"Depletion of myeloid-derived Zbtb46+ cells (adipose tissue DCs) in obese mice improves glucose homeostasis via the DPP4/GLP-1 pathway. Adipose tissue DCs are a key contributor to circulating DPP4 activity; their depletion reduces DPP4 activity, elevates GLP-1 levels, enhances insulin secretion, and decreases food intake. DC-specific Dpp4 knockout confirmed that ATDC-derived DPP4 regulates GLP-1-induced insulin secretion.","method":"Zbtb46-DTR chimeric mice (bone marrow transplant), diphtheria toxin depletion, DC-specific Dpp4 knockout (Cre-loxP), GLP-1/DPP4 activity assays, glucose tolerance testing, insulin assays","journal":"Journal of advanced research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic depletion plus DC-specific KO with defined mechanistic pathway (DPP4/GLP-1), multiple orthogonal genetic approaches in single study","pmids":["41139017"],"is_preprint":false}],"current_model":"ZBTB46 is a BTB-zinc finger transcription factor that enforces classical dendritic cell (cDC) identity by restricting non-DC growth factor responsiveness and suppressing costimulatory molecule expression (CD80/86, CD40) through epigenetic reprogramming via recruitment of NuRD and NCoR/Hdac3 corepressor complexes to target promoters; it is degraded via Cullin1/Fbxw11-mediated ubiquitination upon TLR9 activation to permit DC maturation, controls tumor angiogenesis and myeloid lineage skewing by suppressing Cebpb in bone marrow progenitors, and in non-immune contexts transcriptionally activates LIF and PTGS1 while being regulated by AR/miR-1 signaling to drive EMT and neuroendocrine differentiation in prostate cancer."},"narrative":{"mechanistic_narrative":"ZBTB46 is a BTB-zinc finger transcription factor that enforces classical dendritic cell (cDC) identity and lineage commitment, marking cDCs and committed pre-cDCs but not pDCs, monocytes, or macrophages [PMID:22615127, PMID:22615130]. It restricts cDC responsiveness to non-DC growth factors by silencing G-CSF and LIF receptors, and its enforced expression in bone marrow progenitors suppresses granulocyte/myeloid potential while promoting cDC development [PMID:22615127]. Mechanistically, ZBTB46 binds a 5'-TGACGT-3' motif in the promoters of costimulatory genes (cd80/86, cd40) and maintains them in a repressed, heterochromatic state (H3K4me0/H3K9me3/H3K27me3) by recruiting NuRD and Hdac3/NCoR corepressor complexes; upon TLR9 signaling, Cullin1/Fbxw11-mediated ubiquitination degrades ZBTB46, releasing these promoters for activation and enabling DC maturation [PMID:35675955]. During development, progenitors transit a Zbtb46+Ly6D+ intermediate before acquiring cDC phenotype, a step arrested by type I IFN to favor pDC output [PMID:35705536]. Beyond cDCs, ZBTB46 marks an IL-22-producing ILC3 subset imprinted by RORγt that restrains intestinal inflammation [PMID:35831503], and controls tumor vasculature and myeloid skewing in bone marrow progenitors by suppressing Cebpb, with enforced expression normalizing tumor vessels and synergizing with anti-PD1 therapy [PMID:39134750]. In prostate cancer, ZBTB46 acts as a context-dependent transcriptional regulator induced by androgen deprivation, directly binding and activating LIF, PTGS1, and PCK1 regulatory regions and inducing SNAI1 to drive EMT, LIF-STAT3 signaling, and neuroendocrine differentiation [PMID:28692046, PMID:30312731, PMID:30962287, PMID:34815524].","teleology":[{"year":2012,"claim":"Established that ZBTB46 is a specific marker and master determinant of classical DC identity, resolving how the cDC lineage is distinguished from related myeloid and pDC lineages.","evidence":"GFP/DTR knockin mice, progenitor overexpression, loss-of-function analysis, and in vivo cDC depletion","pmids":["22615127","22615130"],"confidence":"High","gaps":["Direct transcriptional targets and DNA-binding motif not yet defined","Molecular basis for restricting growth-factor receptor expression unresolved"]},{"year":2017,"claim":"Showed ZBTB46 operates outside immunity as an AR/miR-1-regulated driver of EMT in prostate cancer through transcriptional control of SNAI1.","evidence":"miRNA and ZBTB46 gain/loss-of-function, reporter assays, migration/invasion and in vivo tumor models","pmids":["28692046"],"confidence":"Medium","gaps":["Direct vs indirect regulation of SNAI1 not fully resolved by ChIP","Single-lab finding"]},{"year":2018,"claim":"Identified ZBTB46 as a transcriptional coactivator directly binding the PTGS1 promoter within an AR-SPDEF axis, expanding its role in neuroendocrine prostate differentiation.","evidence":"ChIP, overexpression/knockdown, luciferase reporter, tumor models, PTGS1 inhibitor sensitivity","pmids":["30312731"],"confidence":"Medium","gaps":["Coactivator partners not identified","Single lab"]},{"year":2019,"claim":"Demonstrated ZBTB46 directly activates LIF to engage LIF-STAT3 signaling, linking it to neuroendocrine differentiation and high-grade prostate tumors.","evidence":"ChIP at LIF regulatory sequence, gain/loss-of-function, STAT3 signaling assays, patient IHC and serum LIF","pmids":["30962287"],"confidence":"Medium","gaps":["Mechanistic switch from repressor to activator context unclear","Single lab"]},{"year":2020,"claim":"Placed ZBTB46 downstream of an apoptotic-body/STAT5 signaling pathway that tunes DC immune-activating potential.","evidence":"In vitro irradiation, apoptotic body depletion with annexin beads, DC differentiation and cytokine readouts","pmids":["32396024"],"confidence":"Medium","gaps":["Direct STAT5 binding to Zbtb46 locus not shown","Single study"]},{"year":2021,"claim":"Defined ZBTB46's lineage-restricting activity in progenitors, suppressing myeloid/mesoderm programs while favoring erythroid/endothelial output, and identified a PCK1 positive feedback loop in cancer.","evidence":"Inducible ESC overexpression with colony/flow assays; RNA-seq and ChIP for PCK1 regulation in CRPC models","pmids":["34058047","34815524"],"confidence":"Medium","gaps":["Mechanism of erythroid/endothelial promotion undefined","PCK1 feedback loop validated in single lab"]},{"year":2022,"claim":"Provided the molecular mechanism of ZBTB46-mediated repression: motif-specific promoter binding and recruitment of NuRD and Hdac3/NCoR corepressors, with TLR9-induced Cullin1/Fbxw11 degradation switching DCs to a mature state.","evidence":"ChIP-qPCR, mass spectrometry, zebrafish CRISPR KO, co-IP, flow cytometry and T cell assays","pmids":["35675955"],"confidence":"High","gaps":["Demonstrated in zebrafish; mammalian conservation of corepressor recruitment not directly shown","Degron sequence in ZBTB46 not mapped"]},{"year":2022,"claim":"Expanded ZBTB46 function to ILC3 biology and resolved its developmental trajectory, showing it marks an IL-22-producing ILC3 subset and a Ly6D+ cDC intermediate gated by type I IFN.","evidence":"scRNA-seq, conditional depletion, RORγt-dependent imprinting, infection models, cell-fate tracking","pmids":["35831503","35705536"],"confidence":"High","gaps":["Transcriptional targets in ILC3s not defined","How IFN arrests the intermediate stage mechanistically unclear"]},{"year":2024,"claim":"Connected ZBTB46 to tumor angiogenesis and anti-tumor immunity through Cebpb suppression in progenitors and vascular normalization in endothelium, identifying therapeutic synergy with anti-PD1.","evidence":"Cell-type-specific knockout/overexpression, tumor models, Cebpb epistasis, vascular normalization, anti-PD1 combination","pmids":["39134750"],"confidence":"High","gaps":["Direct Cebpb promoter regulation by ZBTB46 not shown","Endothelial transcriptional targets undefined"]},{"year":2025,"claim":"Linked Zbtb46+ adipose-tissue DCs to systemic metabolism via the DPP4/GLP-1 axis, broadening ZBTB46-marked cells to glucose homeostasis.","evidence":"Zbtb46-DTR chimeras, DC-specific Dpp4 knockout, GLP-1/DPP4 and glucose/insulin assays","pmids":["41139017"],"confidence":"High","gaps":["Role of ZBTB46 transcription factor activity itself (vs cell depletion) not separated","DPP4 regulation by ZBTB46 not established"]},{"year":null,"claim":"How the same factor switches between a corepressor (costimulatory silencing) and a coactivator (LIF/PTGS1/PCK1) depending on cell context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ZBTB46 DNA/cofactor complexes","Context-specific cofactor switching mechanism unknown","Human in vivo validation of the corepressor mechanism lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3,4,6,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,4,6,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,5,6,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,4,6,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,7,11]}],"complexes":[],"partners":["NURD","HDAC3","NCOR","HDAC1","HDAC2","CULLIN1","FBXW11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86UZ6","full_name":"Zinc finger and BTB domain-containing protein 46","aliases":["BTB/POZ domain-containing protein 4","Zinc finger protein 340"],"length_aa":589,"mass_kda":64.1,"function":"Transcription regulator that mediates differentiation of conventional and non-conventional dendritic cells, and which is involved in tolerance to gut microbiota. Together with RORgammaT (RORC), specifically expressed in type 3 innate lymphoid cells (ILC3s) that are required for tolerance to gut microbiota, to mediate differentiation of peripherally-induced regulatory T-cells (pTreg), which suppress inflammatory responses to commensal microorganisms. Functions as a transcription corepressor for PRDM1","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q86UZ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZBTB46","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZBTB46","total_profiled":1310},"omim":[{"mim_id":"614639","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 46; ZBTB46","url":"https://www.omim.org/entry/614639"},{"mim_id":"614637","title":"DESUMOYLATING ISOPEPTIDASE 1; DESI1","url":"https://www.omim.org/entry/614637"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":24.1}],"url":"https://www.proteinatlas.org/search/ZBTB46"},"hgnc":{"alias_symbol":["FLJ13502","RINZF","BZEL"],"prev_symbol":["ZNF340","BTBD4"]},"alphafold":{"accession":"Q86UZ6","domains":[{"cath_id":"3.30.710.10","chopping":"15-134","consensus_level":"high","plddt":85.0728,"start":15,"end":134},{"cath_id":"3.30.160.60","chopping":"417-472","consensus_level":"medium","plddt":77.6529,"start":417,"end":472},{"cath_id":"-","chopping":"474-504","consensus_level":"medium","plddt":59.0123,"start":474,"end":504}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86UZ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86UZ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86UZ6-F1-predicted_aligned_error_v6.png","plddt_mean":54.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZBTB46","jax_strain_url":"https://www.jax.org/strain/search?query=ZBTB46"},"sequence":{"accession":"Q86UZ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86UZ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86UZ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86UZ6"}},"corpus_meta":[{"pmid":"22615127","id":"PMC_22615127","title":"Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages.","date":"2012","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22615127","citation_count":522,"is_preprint":false},{"pmid":"22615130","id":"PMC_22615130","title":"Expression of the zinc finger transcription factor zDC (Zbtb46, Btbd4) defines the classical dendritic cell lineage.","date":"2012","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22615130","citation_count":423,"is_preprint":false},{"pmid":"35831503","id":"PMC_35831503","title":"ZBTB46 defines and regulates ILC3s that protect the intestine.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35831503","citation_count":51,"is_preprint":false},{"pmid":"30962287","id":"PMC_30962287","title":"Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46.","date":"2019","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30962287","citation_count":43,"is_preprint":false},{"pmid":"28692046","id":"PMC_28692046","title":"Inhibition of the androgen receptor induces a novel tumor promoter, ZBTB46, for prostate cancer metastasis.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28692046","citation_count":34,"is_preprint":false},{"pmid":"35705536","id":"PMC_35705536","title":"Ly6D+Siglec-H+ precursors contribute to conventional dendritic cells via a Zbtb46+Ly6D+ intermediary stage.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35705536","citation_count":28,"is_preprint":false},{"pmid":"39134750","id":"PMC_39134750","title":"ZBTB46 coordinates angiogenesis and immunity to control tumor outcome.","date":"2024","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39134750","citation_count":23,"is_preprint":false},{"pmid":"30312731","id":"PMC_30312731","title":"Androgen deprivation-induced ZBTB46-PTGS1 signaling promotes neuroendocrine differentiation of prostate cancer.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30312731","citation_count":23,"is_preprint":false},{"pmid":"28161224","id":"PMC_28161224","title":"COX-2 inhibitor prevents tumor induced down regulation of classical DC lineage specific transcription factor Zbtb46 resulting in immunocompetent DC and decreased tumor burden.","date":"2017","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28161224","citation_count":18,"is_preprint":false},{"pmid":"31181727","id":"PMC_31181727","title":"ZBTB46, SPDEF, and ETV6: Novel Potential Biomarkers and Therapeutic Targets in Castration-Resistant Prostate Cancer.","date":"2019","source":"International journal of molecular 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LIF/ZBTB46 signalling in castration-resistant prostate cancer.","date":"2021","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34815524","citation_count":10,"is_preprint":false},{"pmid":"28060909","id":"PMC_28060909","title":"Long-Term Depletion of Conventional Dendritic Cells Cannot Be Maintained in an Atherosclerotic Zbtb46-DTR Mouse Model.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28060909","citation_count":10,"is_preprint":false},{"pmid":"38250572","id":"PMC_38250572","title":"Comparative transcriptomic analysis of Illumina and MGI next-generation sequencing platforms using RUNX3- and ZBTB46-instructed embryonic stem cells.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38250572","citation_count":7,"is_preprint":false},{"pmid":"32396024","id":"PMC_32396024","title":"Radiation-induced augmentation in dendritic cell function is mediated by apoptotic bodies/STAT5/Zbtb46 signaling.","date":"2020","source":"International journal of radiation biology","url":"https://pubmed.ncbi.nlm.nih.gov/32396024","citation_count":3,"is_preprint":false},{"pmid":"34058047","id":"PMC_34058047","title":"Zbtb46-dependent altered developmental program in embryonic stem cell-derived blood cell progenitors.","date":"2021","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/34058047","citation_count":2,"is_preprint":false},{"pmid":"41139017","id":"PMC_41139017","title":"Depletion of myeloid-derived Zbtb46+ cells improves glycemic control in obesity via the DPP4/GLP-1 pathway.","date":"2025","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/41139017","citation_count":0,"is_preprint":false},{"pmid":"41770666","id":"PMC_41770666","title":"Circular RNA ZBTB46 Attenuates Apoptosis and Oxidative Stress in Lipopolysaccharide-Injured Human Endothelial Cells by Modulating ERBB2-AKT Signaling.","date":"2026","source":"Journal of visualized experiments : JoVE","url":"https://pubmed.ncbi.nlm.nih.gov/41770666","citation_count":0,"is_preprint":false},{"pmid":"35953346","id":"PMC_35953346","title":"ZBTB46 in ILC3: shared transcriptional infrastructure defines gut-protective capabilities.","date":"2022","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35953346","citation_count":0,"is_preprint":false},{"pmid":"41868912","id":"PMC_41868912","title":"Long non-coding RNA ZBTB46-AS1 promotes ovarian cancer progression through regulation of p53 activity by TAF6 protein.","date":"2026","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/41868912","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14787,"output_tokens":3872,"usd":0.051221,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11602,"output_tokens":3510,"usd":0.07288,"stage2_stop_reason":"end_turn"},"total_usd":0.124101,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"Zbtb46 is selectively expressed by classical DCs (cDCs) and committed cDC progenitors (pre-cDCs) but not by plasmacytoid DCs, monocytes, macrophages, or other immune lineages. Overexpression of Zbtb46 in bone marrow progenitors inhibited granulocyte potential and promoted cDC development. Zbtb46-deficient cDCs maintained expression of G-CSF and LIF receptors that are normally downregulated in cDCs, indicating Zbtb46 enforces cDC identity by restricting responsiveness to non-DC growth factors.\",\n      \"method\": \"Homologous recombination (GFP knockin), bone marrow progenitor overexpression, Zbtb46-deficient mouse analysis, flow cytometry, developmental potential assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function and gain-of-function with specific cellular phenotypic readouts, replicated across two independent papers in the same issue\",\n      \"pmids\": [\"22615127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"zDC (Zbtb46/Btbd4) is specifically expressed by cDCs and committed cDC precursors but not monocytes, pDCs, or other immune cells. A DTR knockin at the zDC locus allows selective depletion of cDCs upon diphtheria toxin injection, sparing pDCs, monocytes, macrophages, and NK cells.\",\n      \"method\": \"DTR cDNA knockin into zDC locus, diphtheria toxin depletion, flow cytometry, bone marrow chimeras, immune challenge models (T. gondii, melanoma)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockin with functional depletion validated in vivo, replicated in independent lab concurrent with PMID:22615127\",\n      \"pmids\": [\"22615130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZBTB46 is negatively regulated by androgen receptor (AR) signaling via miR-1-mediated downregulation in prostate cancer cells. ZBTB46 transcriptionally regulates SNAI1, a key EMT driver, thereby promoting epithelial-to-mesenchymal transition and metastasis after androgen deprivation.\",\n      \"method\": \"miRNA overexpression/knockdown, ZBTB46 overexpression/knockdown, transcriptional reporter assays, cell migration/invasion assays, in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional loss/gain-of-function with defined downstream target (SNAI1), single lab with multiple methods\",\n      \"pmids\": [\"28692046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZBTB46 acts as a transcriptional coactivator that binds to the promoter of PTGS1 (prostaglandin-endoperoxide synthase 1) and transcriptionally upregulates PTGS1 levels. ZBTB46 is regulated upstream by the androgen-responsive gene SPDEF, placing it in the AR-SPDEF-ZBTB46-PTGS1 axis during neuroendocrine prostate cancer differentiation.\",\n      \"method\": \"ChIP assay (ZBTB46 binding to PTGS1 promoter), ZBTB46 overexpression/knockdown, luciferase reporter, in vitro and in vivo tumor models, PTGS1 inhibitor sensitivity assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus functional overexpression/knockdown, single lab\",\n      \"pmids\": [\"30312731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZBTB46 transcriptionally activates LIF expression in prostate cancer cells by physically interacting with the regulatory sequence of the LIF gene. High ZBTB46 output activates LIF-STAT3 signaling, promoting neuroendocrine differentiation. ZBTB46 is induced by androgen deprivation therapy and is upregulated in high-grade prostate tumors.\",\n      \"method\": \"ChIP assay (ZBTB46 binding to LIF regulatory sequence), ZBTB46 overexpression/knockdown, LIF-STAT3 signaling assays, IHC on patient samples, serum LIF measurement\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct binding to LIF regulatory sequence plus downstream signaling validation, single lab\",\n      \"pmids\": [\"30962287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZBTB46 restrains the inflammatory properties of ILC3s in the intestine, including OX40L-dependent expansion of Th17 cells. ZBTB46 expression in CCR6+ ILC3s is imprinted by RORγt, fine-tuned by microbiota-derived signals, and increased by pro-inflammatory cytokines. ZBTB46+ ILC3s are a major source of IL-22, and their selective depletion renders mice susceptible to enteric infection.\",\n      \"method\": \"Single-cell transcriptomics, conditional cell depletion (DTR-based), genetic loss-of-function, T cell co-culture assays, intestinal infection models (enteric infection), IL-22 measurement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including scRNA-seq, genetic depletion, and in vivo infection models with defined phenotypic readouts, published in Nature\",\n      \"pmids\": [\"35831503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In zebrafish, Zbtb46 binds to a 5'-TGACGT-3' motif in the promoters of cd80/86 and cd40 genes in resting dendritic cells, where it establishes a repressive histone modification pattern (H3K4me0/H3K9me3/H3K27me3) by organizing NuRD (Mdb3/NuRD) and Hdac3/NCoR corepressor complexes through recruitment of Hdac1/2 and Hdac3. Upon TLR9 signaling, E3 ubiquitin ligase Cullin1/Fbxw11 mediates Zbtb46 degradation, releasing promoters for epigenetic reprogramming to an activated state (H3K4me3/H3K9ac/H3K27ac) and enabling CD80/86 and CD40 expression.\",\n      \"method\": \"ChIP-qPCR, mass spectrometry, Zbtb46 knockout zebrafish (CRISPR), co-immunoprecipitation, flow cytometry, T cell activation assays, TLR9 pathway analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP-qPCR identifying binding motif, mass spectrometry identifying corepressor complexes, genetic KO with defined phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"35675955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"During DC development from bone marrow precursors, cDC-primed cells within Ly6DhiZbtb46- precursors rapidly upregulate Zbtb46 and pass through a Zbtb46+Ly6D+ intermediate stage before acquiring cDC phenotype after cell division. Type I IFN arrests cDC-primed cells at the Zbtb46+Ly6D+ stage, limiting cDC output and promoting pDC output.\",\n      \"method\": \"Single-cell transcriptomics, high-dimensional flow cytometry, cell fate analysis (in vitro and in vivo), cytokine stimulation experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-cell transcriptomics combined with cell fate tracking in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"35705536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZBTB46 controls tumor angiogenesis and anti-tumor immunity. In endothelial cells, Zbtb46 deficiency leads to a highly angiogenic phenotype (dysfunctional vasculature). In bone marrow progenitors, Zbtb46 deficiency upregulates Cebpb, diverting DC differentiation toward immunosuppressive myeloid lineage output. Enforced Zbtb46 expression normalizes tumor vessels and, by suppressing Cebpb, skews progenitors toward immunostimulatory myeloid output. Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy.\",\n      \"method\": \"Endothelial cell-specific and bone marrow-specific Zbtb46 knockout/overexpression, in vivo tumor models, transcriptomic analysis, Cebpb epistasis analysis, vascular normalization assays, anti-PD1 combination therapy\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic gain- and loss-of-function with mechanistic pathway identification (Cebpb), in vivo tumor models, published in Nature Immunology\",\n      \"pmids\": [\"39134750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Radiation-induced apoptotic bodies activate STAT5/Zbtb46 signaling in bone marrow progenitors, increasing Zbtb46 expression and enhancing subsequent DC immune-activating potential. Depletion of apoptotic bodies using annexin beads reversed these effects, confirming the apoptotic body → STAT5 → Zbtb46 pathway.\",\n      \"method\": \"In vitro irradiation of bone marrow progenitors, DC differentiation, apoptotic body depletion (annexin beads), flow cytometry, ELISA, adaptive dose experiments in vivo\",\n      \"journal\": \"International journal of radiation biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic/pharmacologic pathway dissection with annexin bead depletion validating the mechanism, single lab, single study\",\n      \"pmids\": [\"32396024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PCK1 (phosphoenolpyruvate carboxykinase 1) is regulated by the ZBTB46 transcription factor upon activation of LIF signaling. ChIP analysis confirmed ZBTB46 binding at PCK1 regulatory regions. Upregulation of PCK1 reciprocally increases ZBTB46 levels, forming a positive feedback loop that promotes neuroendocrine differentiation in CRPC.\",\n      \"method\": \"RNA-seq, ChIP analysis (ZBTB46 binding to PCK1), in vitro cell lines, in vivo animal models, PCK1 inhibitor treatment\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct ZBTB46 binding plus in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"34815524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Forced expression of Zbtb46 in ESC-derived progenitors suppresses myeloid development (reduced CD11b+ cells, lower Irf8 and myeloid gene expression), interferes with mesoderm formation, and inhibits cell proliferation, while promoting erythroid colony formation and increasing adult hemoglobin (Hbb-b1) expression and CD105+ endothelial-like cell formation.\",\n      \"method\": \"Chemically inducible Zbtb46 overexpression in mouse ESC lines, flow cytometry, gene expression profiling, colony assays\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with multiple lineage readouts and transcriptomic profiling, single lab\",\n      \"pmids\": [\"34058047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Depletion of myeloid-derived Zbtb46+ cells (adipose tissue DCs) in obese mice improves glucose homeostasis via the DPP4/GLP-1 pathway. Adipose tissue DCs are a key contributor to circulating DPP4 activity; their depletion reduces DPP4 activity, elevates GLP-1 levels, enhances insulin secretion, and decreases food intake. DC-specific Dpp4 knockout confirmed that ATDC-derived DPP4 regulates GLP-1-induced insulin secretion.\",\n      \"method\": \"Zbtb46-DTR chimeric mice (bone marrow transplant), diphtheria toxin depletion, DC-specific Dpp4 knockout (Cre-loxP), GLP-1/DPP4 activity assays, glucose tolerance testing, insulin assays\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion plus DC-specific KO with defined mechanistic pathway (DPP4/GLP-1), multiple orthogonal genetic approaches in single study\",\n      \"pmids\": [\"41139017\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZBTB46 is a BTB-zinc finger transcription factor that enforces classical dendritic cell (cDC) identity by restricting non-DC growth factor responsiveness and suppressing costimulatory molecule expression (CD80/86, CD40) through epigenetic reprogramming via recruitment of NuRD and NCoR/Hdac3 corepressor complexes to target promoters; it is degraded via Cullin1/Fbxw11-mediated ubiquitination upon TLR9 activation to permit DC maturation, controls tumor angiogenesis and myeloid lineage skewing by suppressing Cebpb in bone marrow progenitors, and in non-immune contexts transcriptionally activates LIF and PTGS1 while being regulated by AR/miR-1 signaling to drive EMT and neuroendocrine differentiation in prostate cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZBTB46 is a BTB-zinc finger transcription factor that enforces classical dendritic cell (cDC) identity and lineage commitment, marking cDCs and committed pre-cDCs but not pDCs, monocytes, or macrophages [#0, #1]. It restricts cDC responsiveness to non-DC growth factors by silencing G-CSF and LIF receptors, and its enforced expression in bone marrow progenitors suppresses granulocyte/myeloid potential while promoting cDC development [#0]. Mechanistically, ZBTB46 binds a 5'-TGACGT-3' motif in the promoters of costimulatory genes (cd80/86, cd40) and maintains them in a repressed, heterochromatic state (H3K4me0/H3K9me3/H3K27me3) by recruiting NuRD and Hdac3/NCoR corepressor complexes; upon TLR9 signaling, Cullin1/Fbxw11-mediated ubiquitination degrades ZBTB46, releasing these promoters for activation and enabling DC maturation [#6]. During development, progenitors transit a Zbtb46+Ly6D+ intermediate before acquiring cDC phenotype, a step arrested by type I IFN to favor pDC output [#7]. Beyond cDCs, ZBTB46 marks an IL-22-producing ILC3 subset imprinted by RORγt that restrains intestinal inflammation [#5], and controls tumor vasculature and myeloid skewing in bone marrow progenitors by suppressing Cebpb, with enforced expression normalizing tumor vessels and synergizing with anti-PD1 therapy [#8]. In prostate cancer, ZBTB46 acts as a context-dependent transcriptional regulator induced by androgen deprivation, directly binding and activating LIF, PTGS1, and PCK1 regulatory regions and inducing SNAI1 to drive EMT, LIF-STAT3 signaling, and neuroendocrine differentiation [#2, #3, #4, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that ZBTB46 is a specific marker and master determinant of classical DC identity, resolving how the cDC lineage is distinguished from related myeloid and pDC lineages.\",\n      \"evidence\": \"GFP/DTR knockin mice, progenitor overexpression, loss-of-function analysis, and in vivo cDC depletion\",\n      \"pmids\": [\"22615127\", \"22615130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets and DNA-binding motif not yet defined\", \"Molecular basis for restricting growth-factor receptor expression unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed ZBTB46 operates outside immunity as an AR/miR-1-regulated driver of EMT in prostate cancer through transcriptional control of SNAI1.\",\n      \"evidence\": \"miRNA and ZBTB46 gain/loss-of-function, reporter assays, migration/invasion and in vivo tumor models\",\n      \"pmids\": [\"28692046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect regulation of SNAI1 not fully resolved by ChIP\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified ZBTB46 as a transcriptional coactivator directly binding the PTGS1 promoter within an AR-SPDEF axis, expanding its role in neuroendocrine prostate differentiation.\",\n      \"evidence\": \"ChIP, overexpression/knockdown, luciferase reporter, tumor models, PTGS1 inhibitor sensitivity\",\n      \"pmids\": [\"30312731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Coactivator partners not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated ZBTB46 directly activates LIF to engage LIF-STAT3 signaling, linking it to neuroendocrine differentiation and high-grade prostate tumors.\",\n      \"evidence\": \"ChIP at LIF regulatory sequence, gain/loss-of-function, STAT3 signaling assays, patient IHC and serum LIF\",\n      \"pmids\": [\"30962287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic switch from repressor to activator context unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed ZBTB46 downstream of an apoptotic-body/STAT5 signaling pathway that tunes DC immune-activating potential.\",\n      \"evidence\": \"In vitro irradiation, apoptotic body depletion with annexin beads, DC differentiation and cytokine readouts\",\n      \"pmids\": [\"32396024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STAT5 binding to Zbtb46 locus not shown\", \"Single study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined ZBTB46's lineage-restricting activity in progenitors, suppressing myeloid/mesoderm programs while favoring erythroid/endothelial output, and identified a PCK1 positive feedback loop in cancer.\",\n      \"evidence\": \"Inducible ESC overexpression with colony/flow assays; RNA-seq and ChIP for PCK1 regulation in CRPC models\",\n      \"pmids\": [\"34058047\", \"34815524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of erythroid/endothelial promotion undefined\", \"PCK1 feedback loop validated in single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the molecular mechanism of ZBTB46-mediated repression: motif-specific promoter binding and recruitment of NuRD and Hdac3/NCoR corepressors, with TLR9-induced Cullin1/Fbxw11 degradation switching DCs to a mature state.\",\n      \"evidence\": \"ChIP-qPCR, mass spectrometry, zebrafish CRISPR KO, co-IP, flow cytometry and T cell assays\",\n      \"pmids\": [\"35675955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demonstrated in zebrafish; mammalian conservation of corepressor recruitment not directly shown\", \"Degron sequence in ZBTB46 not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded ZBTB46 function to ILC3 biology and resolved its developmental trajectory, showing it marks an IL-22-producing ILC3 subset and a Ly6D+ cDC intermediate gated by type I IFN.\",\n      \"evidence\": \"scRNA-seq, conditional depletion, RORγt-dependent imprinting, infection models, cell-fate tracking\",\n      \"pmids\": [\"35831503\", \"35705536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets in ILC3s not defined\", \"How IFN arrests the intermediate stage mechanistically unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected ZBTB46 to tumor angiogenesis and anti-tumor immunity through Cebpb suppression in progenitors and vascular normalization in endothelium, identifying therapeutic synergy with anti-PD1.\",\n      \"evidence\": \"Cell-type-specific knockout/overexpression, tumor models, Cebpb epistasis, vascular normalization, anti-PD1 combination\",\n      \"pmids\": [\"39134750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Cebpb promoter regulation by ZBTB46 not shown\", \"Endothelial transcriptional targets undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked Zbtb46+ adipose-tissue DCs to systemic metabolism via the DPP4/GLP-1 axis, broadening ZBTB46-marked cells to glucose homeostasis.\",\n      \"evidence\": \"Zbtb46-DTR chimeras, DC-specific Dpp4 knockout, GLP-1/DPP4 and glucose/insulin assays\",\n      \"pmids\": [\"41139017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of ZBTB46 transcription factor activity itself (vs cell depletion) not separated\", \"DPP4 regulation by ZBTB46 not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same factor switches between a corepressor (costimulatory silencing) and a coactivator (LIF/PTGS1/PCK1) depending on cell context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ZBTB46 DNA/cofactor complexes\", \"Context-specific cofactor switching mechanism unknown\", \"Human in vivo validation of the corepressor mechanism lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3, 4, 6, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 4, 6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 4, 6, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 7, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NuRD\", \"Hdac3\", \"NCoR\", \"Hdac1\", \"Hdac2\", \"Cullin1\", \"Fbxw11\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}