{"gene":"ZBTB7A","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1997,"finding":"FBI-1 (ZBTB7A) was purified as a cellular factor that specifically binds to the HIV-1 inducer of short transcripts (IST), a bipartite DNA element downstream of the HIV-1 transcriptional start site; binding of FBI-1 to IST correlates with the ability of IST mutants to direct abortive (short) transcript synthesis, suggesting FBI-1 promotes transcription elongation blocks.","method":"Biochemical purification, specific protein-DNA crosslinking, EMSA with IST mutants","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical purification, crosslinking, and functional correlation with IST mutants in a single rigorous study","pmids":["9199312"],"is_preprint":false},{"year":1999,"finding":"FBI-1 (ZBTB7A) contains an N-terminal POZ/BTB domain and four C-terminal Krüppel-type zinc fingers; the C-terminus is sufficient for specific DNA binding, and FBI-1 forms homomers through its POZ domain (and in vivo through its zinc finger domain); FBI-1 also physically associates with HIV-1 Tat protein.","method":"cDNA cloning, domain deletion analysis, in vivo homomer detection, co-immunoprecipitation with Tat","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — cloning plus domain mapping plus co-IP, multiple orthogonal methods in one study, replicated in subsequent literature","pmids":["9973611"],"is_preprint":false},{"year":2002,"finding":"The POZ domain of FBI-1 (ZBTB7A) directly interacts with the zinc finger DNA-binding domain of Sp1, preventing Sp1 from binding GC boxes on the ADH5/FDH promoter, thereby repressing transcription; this mechanism was shared by the POZ domains of PLZF and BCL-6.","method":"GST pull-down (POZ domain fusions), EMSA, DNase I footprinting, ChIP, Gal4 fusion reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution (GST pull-down, DNase I footprinting), ChIP, and reporter assay providing multiple orthogonal lines of evidence","pmids":["12004059"],"is_preprint":false},{"year":2002,"finding":"FBI-1 stimulates HIV-1 Tat-activated transcription; this effect requires the same FBI-1 domain that mediates physical Tat–FBI-1 association in vivo. FBI-1 partially co-localizes with Tat and P-TEFb (Cdk9/CyclinT1) at nuclear speckles, and its nuclear distribution depends on its DNA-binding domain, cellular DNA, and active transcription.","method":"Transcription reporter assay, co-immunoprecipitation, confocal microscopy/immunofluorescence co-localization","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reporter assay plus co-IP plus localization, but single laboratory","pmids":["11907272"],"is_preprint":false},{"year":2003,"finding":"FBI-1 (ZBTB7A) binds to inverted, direct, and everted sequence repeats with the consensus G(A/G)GGG(T/C)(C/T)(T/C)(C/T) with high flexibility in orientation and spacing, indicating highly flexible DNA recognition by a POZ-domain protein.","method":"EMSA with multiple viral and cellular binding sites, sequence analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic EMSA across multiple binding sites, single laboratory","pmids":["12750370"],"is_preprint":false},{"year":2003,"finding":"FBI-1 (ZBTB7A) is induced during early human and murine preadipocyte differentiation and promotes adipogenesis; stably overexpressing FBI-1 in 3T3-L1 cells accelerated differentiation markers and lipid accumulation while reducing DNA synthesis and cyclin A expression, placing FBI-1 as a dual regulator switching cells from proliferation to differentiation.","method":"Stable cell line overexpression, quantification of differentiation markers, lipid accumulation assay, cell proliferation assay, cyclin A protein measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — overexpression gain-of-function with defined cellular phenotypes, single laboratory","pmids":["14701838"],"is_preprint":false},{"year":2005,"finding":"Pokemon/ZBTB7A directly represses ARF tumor suppressor gene transcription through direct promoter binding; mouse embryonic fibroblasts lacking Zbtb7 are completely refractory to oncogene-mediated transformation, and Pokemon overexpression causes oncogenic transformation in vitro and in transgenic mice.","method":"ChIP, promoter reporter assay, MEF transformation assay, Zbtb7 knockout MEFs, transgenic mouse model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct promoter binding (ChIP), loss-of-function (KO MEFs), gain-of-function (transgenic mice), multiple orthogonal methods, replicated by multiple subsequent studies","pmids":["15662416"],"is_preprint":false},{"year":2005,"finding":"FBI-1 (ZBTB7A) interacts with the Rel homology domain of NF-κB p65 via its POZ domain in vivo and in vitro, enhances NF-κB-mediated E-selectin gene transcription, promotes nuclear localization and stability of p65, and also interacts with IκBα and IκBβ.","method":"Co-immunoprecipitation (in vivo and in vitro protein-protein interaction), luciferase reporter assay, confocal microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus reporter assay plus imaging, single laboratory","pmids":["15917220"],"is_preprint":false},{"year":2006,"finding":"The BTB/POZ domain of human LRF/ZBTB7A adopts the canonical BTB homodimer fold; the lateral groove and charged pocket on the homodimer surface differ substantially from BCL6 BTB, and the 17-residue BCL6 Binding Domain (BBD) of SMRT co-repressor does not bind to the LRF BTB domain.","method":"X-ray crystallography (2.1 Å), in vitro binding assay (BBD peptide binding test)","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.1 Å with functional validation (negative binding result for SMRT BBD), single but rigorous study","pmids":["17189472"],"is_preprint":false},{"year":2008,"finding":"FBI-1 (ZBTB7A) represses Rb gene transcription by binding to four GC-rich FBI-1-response elements (FREs) in the Rb promoter and by competing with Sp1 at GC-box 2 and FRE3; repression involves recruitment of a co-repressor–HDAC complex through the POZ domain, leading to deacetylation of H3 and H4 histones at the Rb promoter. FBI-1 also inhibits C2C12 myoblast differentiation by repressing Rb.","method":"ChIP, EMSA, luciferase reporter assay, site-directed mutagenesis, histone deacetylation assay, myoblast differentiation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP plus EMSA plus mutagenesis plus functional differentiation assay, multiple orthogonal methods","pmids":["18801742"],"is_preprint":false},{"year":2008,"finding":"FBI-1 (ZBTB7A) and SREBP-1 interact directly via their DNA-binding domains and synergistically activate FASN gene transcription; FBI-1 alters the binding pattern of Sp1 and SREBP-1 on GC-box and SRE/E-box elements to drive higher Sp1 binding to the proximal FASN promoter.","method":"Co-immunoprecipitation, luciferase reporter assay, ChIP, EMSA, co-transfection experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus reporter assay, single laboratory","pmids":["18682402"],"is_preprint":false},{"year":2008,"finding":"FBI-1 (ZBTB7A) acts as a dual regulator in adipogenesis: it represses cyclin A through an indirect mechanism (inhibiting Sp1 binding at the cyclin A promoter) and represses E2F-4 directly via a FBI-1 binding element; FBI-1 binds Sin3A and HDAC-1 to form a repressor complex through its POZ domain.","method":"Luciferase reporter assay, EMSA, co-immunoprecipitation, site-directed mutagenesis, POZ domain deletion mutants","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, EMSA, mutagenesis, reporter assay, single laboratory","pmids":["18368381"],"is_preprint":false},{"year":2009,"finding":"FBI-1 (ZBTB7A) represses p21CIP1 transcription by direct binding to the proximal Sp1-3 GC-box and distal p53-responsive elements, competing with both Sp1 and p53; it also recruits co-repressors mSin3A, NCoR, and SMRT, leading to deacetylation of Ac-H3 and Ac-H4 histones at the p21 promoter. FBI-1 functions as a master controller of the ARF–Hdm2–p53–p21 pathway.","method":"ChIP, EMSA, luciferase reporter assay, co-immunoprecipitation, histone deacetylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, EMSA, co-IP, mutagenesis), consistent with prior findings on FBI-1 repressor mechanism","pmids":["19244234"],"is_preprint":false},{"year":2009,"finding":"eEF1A/CCS-3 directly interacts with FBI-1 (ZBTB7A) through both the zinc finger and POZ domains of FBI-1; CCS-3 enhances FBI-1-mediated transcriptional repression of p21CIP1 by facilitating interaction with co-repressors SMRT and BCoR at the POZ domain.","method":"Co-immunoprecipitation, GST pull-down, MALDI-TOF mass spectrometry, immunofluorescence co-localization, luciferase reporter assay","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pull-down plus co-IP plus reporter assay, single laboratory","pmids":["19471103"],"is_preprint":false},{"year":2010,"finding":"FBI-1 (ZBTB7A) acts as a co-repressor of the androgen receptor (AR) in prostate cancer cells; FBI-1 physically interacts with AR in a ligand-dependent manner and forms a ternary complex with AR and SMRT, enhancing recruitment of NCoR and SMRT to endogenous PSA upstream sequences. FBI-1-mediated inhibition of AR transcriptional activity is partially dependent on HDAC activity.","method":"Co-immunoprecipitation, ChIP, luciferase reporter assay, HDAC inhibitor treatment","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus reporter assay, single laboratory","pmids":["20812024"],"is_preprint":false},{"year":2011,"finding":"ZBTB7A/LRF (FBI-1/OCZF) is expressed in osteoclasts, is upregulated by RANKL in primary macrophages, and is required for RANKL-induced osteoclast formation in vitro; transgenic mice overexpressing OCZF under the cathepsin K promoter show decreased bone volume, increased osteoclast number, and promoted osteoclast survival.","method":"Immunostaining, in situ hybridization, transgenic mouse model (OCZF-Tg), siRNA knockdown of LRF in osteoclast differentiation assay, bone histomorphometry, pQCT","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse model plus in vitro knockdown plus histomorphometry, multiple independent methods","pmids":["21590684"],"is_preprint":false},{"year":2011,"finding":"Pokemon/ZBTB7A directly binds GT boxes in the survivin promoter and induces survivin expression in breast cancer cells; ChIP and site-directed mutagenesis confirmed direct promoter binding.","method":"ChIP, site-directed mutagenesis, DNA microarray, luciferase reporter","journal":"Breast cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus mutagenesis plus microarray, single laboratory","pmids":["21392388"],"is_preprint":false},{"year":2011,"finding":"FBI-1 (ZBTB7A) directly activates MT1-MMP promoter transcription by binding the ~600 bp 5'-flanking sequence of MT1-MMP (confirmed by promoter reporter assay and ChIP), leading to enhanced cancer cell migration and invasion; MT1-MMP knockdown abolished FBI-1-mediated invasion.","method":"ChIP, promoter reporter assay (promoter deletion constructs), siRNA knockdown of MT1-MMP, invasion/migration assay","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus epistasis (MT1-MMP KD rescues phenotype), single laboratory","pmids":["21176152"],"is_preprint":false},{"year":2012,"finding":"Pokemon/ZBTB7A directly binds the Bim promoter and suppresses Bim transcription, rendering liver cells resistant to anoikis; Pokemon knockdown enhances sensitivity to anoikis and chemical apoptotic stress, while ectopic Pokemon expression confers anoikis resistance.","method":"Dual-luciferase reporter assay, ChIP, siRNA knockdown, flow cytometry, caspase-3 activity assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus gain/loss-of-function, single laboratory","pmids":["22754333"],"is_preprint":false},{"year":2012,"finding":"Pokemon/ZBTB7A directly binds the p65 promoter element at -434 to -430 bp and the IκBα promoter element at -453 to -448 bp, activating transcription of both, revealing a homeostatic regulatory role in NF-κB signaling.","method":"ChIP, targeted mutagenesis, luciferase reporter assay, siRNA knockdown","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus mutagenesis plus reporter assay, single laboratory","pmids":["23054188"],"is_preprint":false},{"year":2013,"finding":"FBI-1 (ZBTB7A) directly interacts with MBD3 in the nucleus; through MBD3, FBI-1 recruits the Mi-2/NuRD-HDAC complex to the CDKN1A promoter for epigenetic repression; MBD3 modulates FBI-1 interactions with co-repressors (decreasing NCoR/SMRT interaction, increasing BCoR interaction); BCoR links to DNMTs and HP1, enabling DNA methylation-based silencing of p21WAF/CDKN1A.","method":"Co-immunoprecipitation, ChIP, EMSA (methylated and non-methylated DNA binding), luciferase reporter assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-IP plus ChIP plus EMSA plus reporter assay, multiple orthogonal methods revealing epigenetic mechanism","pmids":["23658227"],"is_preprint":false},{"year":2013,"finding":"ZBTB7A physically interacts with SOX9 and functionally antagonizes SOX9 transcriptional activity on target genes MIA (tumor invasion) and H19 (lncRNA precursor for RB-targeting miRNA); prostate-specific Zbtb7a inactivation accelerates Pten loss-driven tumorigenesis through bypass of Pten loss-induced cellular senescence, Rb downregulation, and invasive cancer.","method":"Co-immunoprecipitation (physical interaction), conditional knockout mouse model (prostate-specific), RT-PCR/Western blot of target gene expression, histopathological analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-IP plus conditional KO mouse model plus target gene analysis, multiple orthogonal methods in one study","pmids":["23727861"],"is_preprint":false},{"year":2013,"finding":"Pokemon/ZBTB7A silencing in HCC inhibits the PI3K/Akt and c-Raf/MEK/ERK pathways and modulates cell cycle regulators, suppressing cell proliferation and migration in vitro and tumor growth in xenograft mice.","method":"Stable shRNA knockdown, Western blot (pathway markers), cell proliferation and migration assays, xenograft mouse model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — stable KD plus pathway marker analysis plus in vivo model, single laboratory","pmids":["23300578"],"is_preprint":false},{"year":2013,"finding":"Pokemon/ZBTB7A directly binds the miR-21 promoter at GC boxes (-684 to -679 bp and -652 to -647 bp) and upregulates miR-21 transcription, which in turn suppresses Sprouty1 (a miR-21 target); site-directed mutagenesis of GC boxes abolished Pokemon regulation of miR-21.","method":"ChIP, luciferase reporter assay, site-directed mutagenesis, siRNA","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus mutagenesis plus reporter assay, single laboratory","pmids":["23355454"],"is_preprint":false},{"year":2014,"finding":"ZBTB7A directly binds to the promoters of key glycolytic genes GLUT3, PFKP, and PKM and transcriptionally represses them; ZBTB7A-deficient tumors exhibit elevated glycolysis and heightened sensitivity to glycolysis inhibition.","method":"ChIP, luciferase reporter assay, metabolic assays, ZBTB7A loss-of-function (KO/KD) in cell lines and mouse models, TCGA data analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct ChIP plus reporter assay plus metabolic functional readout plus in vivo model, multiple orthogonal methods","pmids":["25184678"],"is_preprint":false},{"year":2014,"finding":"FBI-1 (ZBTB7A) interacts with the splicing factor SAM68 and reduces SAM68 binding to BCL-X mRNA, shifting BCL-X alternative splicing toward the anti-apoptotic BCL-XL variant and counteracting SAM68-mediated apoptosis; this splicing role requires HDAC activity.","method":"Co-immunoprecipitation, RNA immunoprecipitation, RT-PCR splicing assay, FBI-1 knockdown, SAM68 interaction-domain mutant, HDAC inhibitor treatment","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-IP plus RIP plus splicing assay plus domain mutant plus pharmacological validation, multiple orthogonal methods in one study","pmids":["24514149"],"is_preprint":false},{"year":2014,"finding":"Pokemon/ZBTB7A directly interacts with Smad4, and this interaction is enhanced by TGF-β1 treatment; Pokemon overexpression decreases TGF-β-induced transcriptional activities by recruiting HDAC1 to the Smad4 complex and reducing Smad4–p300/CBP interaction, without affecting Smad2/3 activation or Smad complex formation.","method":"Co-immunoprecipitation (in vitro and in vivo), luciferase reporter assay, ChIP (Pokemon recruitment to Smad4-DNA complex), Western blot","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus reporter assay, single laboratory","pmids":["25514493"],"is_preprint":false},{"year":2014,"finding":"FBI-1 (ZBTB7A) physically interacts with ETS-1, promotes ETS-1 nuclear accumulation, and enhances ETS-1 recruitment to target gene promoters; this occurs partly by FBI-1 downregulating p53-mediated inhibition of ETS-1.","method":"Co-immunoprecipitation, ChIP, luciferase reporter assay","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP plus ChIP, single laboratory, limited mechanistic follow-up","pmids":["24857950"],"is_preprint":false},{"year":2015,"finding":"ZBTB7A directly binds the MCAM promoter and transcriptionally represses MCAM expression; loss of ZBTB7A leads to upregulation of MCAM and enhanced melanoma cell invasion and metastasis.","method":"ChIP, promoter reporter assay, loss-of-function (ZBTB7A KD), invasion/metastasis assays, human melanoma specimen analysis","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus functional invasion assay, single laboratory","pmids":["25995384"],"is_preprint":false},{"year":2015,"finding":"Zinc finger domain mutations in ZBTB7A (identified in human cancers) result in loss of DNA-binding function; cells harboring these mutations show marked upregulation of glycolytic target genes (GLUT3, PFKP, PKM), increased glycolysis, and enhanced proliferation.","method":"Site-directed mutagenesis of zinc finger domain, luciferase reporter assay, metabolic assays, cell proliferation assay, cancer genome database mining","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus reporter assay plus metabolic functional readout, single laboratory but rigorous functional characterization","pmids":["26455326"],"is_preprint":false},{"year":2016,"finding":"Recurrent ZBTB7A mutations (missense and truncating) affecting the C-terminal zinc-finger domain occur in 23% of AML t(8;21) patients; these mutations disrupt the transcriptional repressor activity and anti-proliferative effect of ZBTB7A, and their specific association with t(8;21) AML indicates leukaemogenic cooperativity with RUNX1/RUNX1T1.","method":"Sequencing of patient samples, functional luciferase reporter assay (repressor activity), proliferation assay of mutant ZBTB7A-expressing cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — patient-derived mutations functionally validated in reporter assay and proliferation assay, replicated across 56 patients","pmids":["27252013"],"is_preprint":false},{"year":2017,"finding":"KLF1 directly drives ZBTB7A expression in erythroid cells by binding to the ZBTB7A proximal promoter (confirmed by ChIP); an erythroid-specific regulatory mechanism upregulates a novel ZBTB7A transcript in the erythroid compartment.","method":"ChIP, promoter analysis, RT-PCR of novel transcript, erythroid cell differentiation system","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus transcript analysis, single laboratory","pmids":["29296711"],"is_preprint":false},{"year":2017,"finding":"ZBTB7A directly binds the LINC00473 promoter and transcriptionally represses LINC00473 expression in osteosarcoma; LINC00473 interacts with transcription factor C/EBPβ, facilitating its binding to the IL24 promoter to decrease chemoresistance.","method":"ChIP, luciferase reporter assay, siRNA knockdown, RNA immunoprecipitation","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus RNA-IP, single laboratory","pmids":["28942243"],"is_preprint":false},{"year":2017,"finding":"Zbtb7a induction in alveolar macrophages (AMs) is a critical early event in DSA-induced chronic lung allograft rejection; selective disruption of Zbtb7a in AMs reduced bronchiolar occlusion and immune responses to lung-restricted self-antigens; antigen presentation by AMs is Zbtb7a-dependent, as Zbtb7a-deficient AMs failed to induce antibody and T cell responses.","method":"Conditional macrophage-specific Zbtb7a knockout, murine obliterative airway disease model, adoptive transfer, immunological readouts (antibody and T cell responses)","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO plus in vivo model plus mechanistic immune readouts, replicated in mouse and human correlation","pmids":["28701473"],"is_preprint":false},{"year":2018,"finding":"ZBTB7A directly binds the γ-globin gene promoter at the -200 bp region (containing two copies of four consecutive C:G base pairs) and acts as a major direct repressor of fetal HBG1/HBG2 (γ-globin) gene expression; naturally occurring HPFH-associated point mutations at -200 bp disrupt ZBTB7A binding and elevate γ-globin expression.","method":"CRISPR-Cas9 introduction of HPFH mutations, ChIP, EMSA, erythroid cell reporter assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR functional mutation plus ChIP plus EMSA, multiple orthogonal methods, replicated in structural study (PMID 34592153)","pmids":["29610478"],"is_preprint":false},{"year":2018,"finding":"HP1γ (CBX3) directly represses ZBTB7A expression in lung adenocarcinoma cells; knockdown of ZBTB7A significantly restores the proliferation, colony formation, and migration defects caused by HP1γ depletion, placing ZBTB7A downstream of HP1γ in a lung adenocarcinoma-promoting pathway; ZBTB7A in turn downregulates AXL expression.","method":"siRNA knockdown (HP1γ and ZBTB7A), epistasis rescue experiment, ChIP (HP1γ on ZBTB7A locus), cell proliferation/colony/migration assays, in vivo K-RasG12D mouse model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue plus ChIP plus in vivo model, single laboratory","pmids":["29764865"],"is_preprint":false},{"year":2018,"finding":"Zbtb7a binds to a significant fraction of genomic promoters and enhancers genome-wide; it is required for inducible changes in chromatin accessibility driven by NF-κB p65 and other transcription factors (TFs); Zbtb7a associates with promoters independently of client TF binding and specifies promoters amenable to TF-induced accessibility changes, acting as an accessibility transducer.","method":"ChIP-seq, ATAC-seq, RNA-seq, Zbtb7a knockdown, p65 induction experiments in macrophages","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide ChIP-seq plus ATAC-seq plus RNA-seq plus functional KD, multiple orthogonal genome-scale methods","pmids":["29813070"],"is_preprint":false},{"year":2019,"finding":"ZBTB7A mediates AR-dependent transcriptional repression in prostate cancer cells; ZBTB7A is recruited to E2F-Rb binding sites by AR and negatively regulates E2F1 transcriptional activity on DNA replication genes; AR recruitment of Rb strengthens the E2F-Rb repression complex; ZBTB7A suppresses castration-resistant prostate cancer growth in vitro and in vivo.","method":"ChIP-seq, RNA-seq, siRNA knockdown, co-immunoprecipitation, in vitro and xenograft in vivo assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP-seq plus RNA-seq plus co-IP plus functional in vivo model, multiple orthogonal methods in one study","pmids":["31444154"],"is_preprint":false},{"year":2019,"finding":"Under hypoxia, NF-κB (RelA/p65) binds NF-κB-binding elements in the ZBTB7A promoter and represses ZBTB7A expression, thereby de-repressing SLC16A3 (MCT4); FBI-1/ZBTB7A directly represses SLC16A3 by binding both FREs and HREs in the SLC16A3 promoter during normoxia.","method":"Transient transfection/reporter assay of SLC16A3 and ZBTB7A promoter constructs, oligonucleotide pulldown, ChIP","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus oligonucleotide pulldown, single laboratory","pmids":["31271899"],"is_preprint":false},{"year":2019,"finding":"ZBTB7A transcriptionally regulates ERα (ESR1) expression in ERα-positive breast cancer by binding the ESR1 promoter (+146 to +461 bp downstream of TSS), and inhibition of ZBTB7A upregulates E3 ligase TRIM25, enhancing ERα ubiquitination and proteasomal degradation; ERα in turn potentiates ZBTB7A expression post-translationally, forming a positive feedback loop.","method":"ChIP, luciferase reporter assay, siRNA knockdown, TRIM25 co-IP/ubiquitination assay, estrogen-response element reporter","journal":"Journal of molecular cell biology / Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus ubiquitination assay, single laboratory","pmids":["30265334","31715186"],"is_preprint":false},{"year":2019,"finding":"ZBTB7A directly binds the LncRNA GAS5 promoter and transcriptionally suppresses GAS5 expression in osteosarcoma cells, reducing ER stress-induced apoptosis; miR-663a (induced by ER stress) directly targets the 3'UTR of ZBTB7A to downregulate it.","method":"ChIP, luciferase reporter assay, miRNA 3'UTR reporter assay, siRNA knockdown, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus functional in vivo readout, single laboratory","pmids":["30753838"],"is_preprint":false},{"year":2020,"finding":"BMP4 signaling opens chromatin at Zbtb7a/b loci early during primed-to-naive pluripotency transition (PNT); ZBTB7A in turn occupies and facilitates opening of naive pluripotent chromatin loci (activating nearby genes) while also occupying loci that are silenced, consistent with dual roles in chromatin remodeling during PNT.","method":"ATAC-seq (chromatin accessibility), ChIP-seq (ZBTB7A binding), RNA-seq, BMP4-driven PNT system, ZBTB7A overexpression/knockdown","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ATAC-seq plus ChIP-seq plus RNA-seq plus gain/loss-of-function in a defined differentiation system","pmids":["32393886"],"is_preprint":false},{"year":2020,"finding":"Wild-type ZBTB7A prevents RUNX1-RUNX1T1 (AML1-ETO)-mediated clonal expansion of human CD34+ hematopoietic stem and progenitor cells; ZBTB7A mutations enable this clonal expansion. ZBTB7A loss increases glycolysis and sensitizes t(8;21) leukemic blasts to 2-deoxy-D-glucose. ZBTB7A expression in t(8;21) cells causes cell cycle arrest recapitulated by glycolysis inhibition.","method":"Lentiviral expression of WT/mutant ZBTB7A in CD34+ cells, clonal expansion assay, Seahorse metabolic assay, cell cycle analysis, 2-DG treatment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — primary human CD34+ cell model plus metabolic assays plus cell cycle analysis, multiple orthogonal methods","pmids":["32115572"],"is_preprint":false},{"year":2021,"finding":"X-ray crystal structures of the ZBTB7A DNA-binding domain (four zinc fingers) in complex with the γ-globin promoter -200 bp element reveal that ZF1 and ZF2 recognize the 5' C:G quadruple and ZF4 contacts the 3' C:G quadruple; HPFH-associated mutations that impair ZBTB7A binding most severely disrupt base pairs recognized by ZF1 and ZF2.","method":"X-ray crystallography, in vitro DNA-binding assays with HPFH mutant sequences","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus functional binding assays with disease-relevant mutations, highly rigorous single study","pmids":["34592153"],"is_preprint":false},{"year":2022,"finding":"CRISPR activation screen identified ZBTB7A as a factor that, when upregulated, promotes cell survival and allows HCoV-229E to establish a persistent homeostatic infection rather than causing cell death; control of oxidative stress is a primary driver of cellular survival during HCoV-229E infection downstream of ZBTB7A.","method":"CRISPR activation screen, viral infection assay (HCoV-229E), cell viability assay, oxidative stress measurement","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus functional viral infection validation, single laboratory","pmids":["36243002"],"is_preprint":false},{"year":2023,"finding":"ZBTB7A directly binds the EPB41L5 gene promoter and represses its transcription in glioblastoma cells; ZBTB7A depletion induces GBM progression and metastasis, while ZBTB7A expression dramatically inhibits GBM tumor growth by suppressing EPB41L5-driven EMT.","method":"RNA-seq (ZBTB7A-depleted vs. control), ChIP (ZBTB7A binding to EPB41L5 promoter), loss-of-function (siRNA/shRNA), in vitro invasion assay, in vivo tumor growth assay","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus RNA-seq plus functional in vivo assay, single laboratory","pmids":["36596853"],"is_preprint":false},{"year":2023,"finding":"ZBTB7A directly binds the promoter regions of HK2 and LDHA, transcriptionally inhibiting their expression; small nucleolar RNA-derived fragment U3-miR reduces ZBTB7A mRNA stability (via ZBTB7A 3'UTR binding), thereby releasing HK2/LDHA repression and enhancing aerobic glycolysis in IDH1-wild-type glioblastoma cells.","method":"ChIP (ZBTB7A on HK2 and LDHA promoters), luciferase 3'UTR reporter assay, Seahorse glycolysis assay, siRNA knockdown","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus metabolic functional assay, single laboratory","pmids":["37066523"],"is_preprint":false}],"current_model":"ZBTB7A (FBI-1/LRF/Pokemon) is a BTB-zinc finger transcriptional repressor that homodimerizes through its POZ/BTB domain, binds GC-rich DNA elements via four C-terminal zinc fingers, and represses a broad set of target genes (ARF, RB, p21/CDKN1A, glycolytic enzymes GLUT3/PFKP/PKM/HK2/LDHA, MCAM, fetal γ-globin/HBG, MT1-MMP, BCL-2 family members, and others) by recruiting co-repressor–HDAC complexes (NCoR, SMRT, BCoR, Sin3A, Mi-2/NuRD) and promoting histone deacetylation and, in some contexts, DNA methylation; it also regulates alternative splicing of BCL-X by interacting with SAM68, modulates NF-κB and AR signaling through direct protein–protein interactions, controls chromatin accessibility at promoters/enhancers genome-wide as an accessibility transducer for multiple transcription factors, acts as a direct repressor of fetal globin genes (binding the γ-globin -200 bp promoter element through ZF1/ZF2/ZF4) whose structural basis has been resolved crystallographically, and has context-dependent oncogenic or tumor-suppressive roles depending on cancer type and interacting genetic lesions."},"narrative":{"mechanistic_narrative":"ZBTB7A (FBI-1/LRF/Pokemon) is a sequence-specific BTB-zinc finger transcription factor that controls cell proliferation, differentiation, metabolism, and lineage-specific gene programs, acting predominantly as a transcriptional repressor while also functioning as a genome-wide chromatin accessibility transducer [PMID:15662416, PMID:25184678, PMID:29813070]. It is built from an N-terminal POZ/BTB domain that mediates homodimerization and a C-terminal array of four Krüppel-type zinc fingers that confer specific binding to GC-rich elements with flexible orientation and spacing [PMID:9973611, PMID:12750370]. Through its POZ domain it recruits corepressor–HDAC machinery (Sin3A/HDAC1, NCoR, SMRT, BCoR) to silence target promoters, drive histone H3/H4 deacetylation, and—via MBD3-dependent recruitment of the Mi-2/NuRD complex linked to DNMTs and HP1—impose DNA-methylation-based silencing [PMID:18801742, PMID:18368381, PMID:19244234, PMID:23658227]. The same POZ surface also directly competes with or sequesters other DNA-binding factors, including Sp1 at GC boxes, p53 at responsive elements, and SOX9, redirecting promoter occupancy [PMID:12004059, PMID:19244234, PMID:23727861]. Through this repertoire ZBTB7A represses cell-cycle and tumor-suppressor genes including ARF, Rb, and p21/CDKN1A, positioning it as a controller of the ARF–p53–p21 axis whose overexpression transforms cells and whose loss bypasses senescence [PMID:15662416, PMID:18801742, PMID:19244234, PMID:23727861]. ZBTB7A is a master repressor of glycolysis, binding and silencing GLUT3, PFKP, PKM, HK2, and LDHA, such that loss-of-function elevates aerobic glycolysis and sensitizes tumors to glycolytic inhibition [PMID:25184678, PMID:26455326, PMID:37066523]. In erythroid cells it is induced by KLF1 and directly represses fetal γ-globin (HBG1/HBG2) by binding two C:G quadruplets in the -200 bp promoter through ZF1, ZF2, and ZF4, a recognition mode resolved crystallographically and disrupted by HPFH point mutations [PMID:29296711, PMID:29610478, PMID:34592153]. Beyond classical repression, ZBTB7A modulates partner transcription factors and signaling through direct protein–protein interactions with NF-κB p65, the androgen receptor, Smad4, ETS-1, and SREBP-1, and regulates BCL-X alternative splicing by interacting with SAM68 [PMID:15917220, PMID:18682402, PMID:20812024, PMID:24514149, PMID:25514493, PMID:31444154]. Recurrent zinc-finger mutations that abolish DNA binding occur in t(8;21) AML and cooperate with RUNX1-RUNX1T1 to permit clonal expansion of hematopoietic progenitors, while context-dependent roles render ZBTB7A oncogenic or tumor-suppressive across cancer types [PMID:26455326, PMID:27252013, PMID:32115572].","teleology":[{"year":1997,"claim":"Established ZBTB7A as a sequence-specific DNA-binding factor by identifying it as the cellular protein recognizing the HIV-1 IST element and linking its binding to transcriptional elongation control.","evidence":"Biochemical purification, protein-DNA crosslinking, and EMSA with IST mutants","pmids":["9199312"],"confidence":"High","gaps":["Did not define the protein's domain architecture","Cellular target genes beyond the viral element unknown"]},{"year":1999,"claim":"Defined the bipartite architecture—N-terminal POZ/BTB domain mediating homomerization and four C-terminal zinc fingers sufficient for DNA binding—and showed physical association with HIV-1 Tat.","evidence":"cDNA cloning, domain deletion analysis, in vivo homomer detection, co-IP with Tat","pmids":["9973611"],"confidence":"High","gaps":["Cellular corepressor partners not yet identified","DNA consensus not yet systematically defined"]},{"year":2002,"claim":"Revealed a non-canonical repression mode in which the POZ domain directly binds the Sp1 DNA-binding domain to evict Sp1 from GC boxes, establishing competitive repression independent of ZBTB7A's own DNA binding.","evidence":"GST pull-down, EMSA, DNase I footprinting, ChIP, and Gal4 reporter assay on ADH5/FDH promoter","pmids":["12004059"],"confidence":"High","gaps":["Generality of Sp1 competition across promoters untested at the time","HDAC recruitment not yet shown"]},{"year":2003,"claim":"Characterized the flexible GC-rich consensus ZBTB7A recognizes and showed its induction promotes adipocyte differentiation while suppressing proliferation, framing it as a proliferation-to-differentiation switch.","evidence":"EMSA across binding sites; overexpression in 3T3-L1 with differentiation, lipid, and proliferation readouts","pmids":["12750370","14701838"],"confidence":"Medium","gaps":["Adipogenesis data are overexpression gain-of-function","Direct target genes driving the differentiation switch not fully mapped"]},{"year":2005,"claim":"Defined ZBTB7A as a bona fide proto-oncogene by showing direct ARF repression, that its loss renders fibroblasts refractory to transformation, and that overexpression transforms cells and mice.","evidence":"ChIP, reporter assay, Zbtb7 KO MEF transformation assay, transgenic mouse model","pmids":["15662416"],"confidence":"High","gaps":["Did not resolve the context-dependence (oncogene vs tumor suppressor) seen in later studies","Corepressor complex composition at ARF not detailed"]},{"year":2005,"claim":"Showed ZBTB7A also engages signaling transcription factors directly, binding NF-κB p65 via its POZ domain to enhance p65 stability and target gene transcription.","evidence":"Reciprocal co-IP, luciferase reporter, confocal microscopy","pmids":["15917220"],"confidence":"Medium","gaps":["Single-laboratory interaction data","Whether p65 regulation is direct transcriptional or purely stability-based not fully separated"]},{"year":2006,"claim":"Established the structural basis of POZ/BTB homodimerization and demonstrated that the LRF BTB surface diverges from BCL6, explaining why the SMRT BCL6-binding peptide does not engage it.","evidence":"X-ray crystallography at 2.1 Å plus BBD peptide binding assay","pmids":["17189472"],"confidence":"High","gaps":["Did not identify the actual corepressor-recruitment surface used by LRF","No DNA-bound structure"]},{"year":2008,"claim":"Mechanistically linked ZBTB7A repression to corepressor-HDAC recruitment, showing Rb, p21, cyclin A, and E2F-4 silencing through POZ-mediated Sin3A/HDAC1 binding, histone deacetylation, and Sp1 competition.","evidence":"ChIP, EMSA, reporter assays, mutagenesis, histone deacetylation and differentiation assays","pmids":["18801742","18368381"],"confidence":"High","gaps":["Distinction between direct binding and Sp1 competition at each target not always resolved","In vivo relevance to differentiation tested only in cell models"]},{"year":2008,"claim":"Demonstrated context-dependent transcriptional activation, with ZBTB7A directly partnering SREBP-1 to synergistically activate FASN by remodeling Sp1/SREBP-1 promoter occupancy.","evidence":"Co-IP, ChIP, EMSA, reporter and co-transfection assays","pmids":["18682402"],"confidence":"Medium","gaps":["Single-laboratory finding","How the repressor switches to a coactivator mode mechanistically unresolved"]},{"year":2009,"claim":"Positioned ZBTB7A as a master controller of the ARF–Hdm2–p53–p21 axis through direct p21 repression involving competition with both Sp1 and p53 and recruitment of mSin3A/NCoR/SMRT.","evidence":"ChIP, EMSA, reporter assays, co-IP, histone deacetylation assay; plus eEF1A/CCS-3 corepressor-bridging study","pmids":["19244234","19471103"],"confidence":"High","gaps":["CCS-3 bridging interaction not independently replicated","Relative contribution of Sp1 vs p53 competition not quantified"]},{"year":2010,"claim":"Extended ZBTB7A's interactome to nuclear receptors, showing ligand-dependent corepression of the androgen receptor via a ternary AR–ZBTB7A–SMRT complex and HDAC-dependent inhibition.","evidence":"Co-IP, ChIP, reporter assays, HDAC inhibitor treatment in prostate cancer cells","pmids":["20812024"],"confidence":"Medium","gaps":["Single-laboratory interaction data","Endogenous target gene scope limited to PSA"]},{"year":2011,"claim":"Identified tissue-specific roles in bone and demonstrated activating as well as repressive functions in cancer, showing requirement for RANKL-induced osteoclastogenesis and direct activation of survivin and MT1-MMP to promote invasion.","evidence":"Transgenic mouse, siRNA knockdown, histomorphometry; ChIP, mutagenesis, reporter, invasion assays","pmids":["21590684","21392388","21176152"],"confidence":"High","gaps":["Mechanistic basis for activation vs repression at different promoters not unified","Survivin and MT1-MMP activation from single laboratories"]},{"year":2012,"claim":"Showed ZBTB7A enforces survival and apoptosis resistance by directly repressing the pro-apoptotic Bim gene and by acting in a homeostatic NF-κB feedback loop activating p65 and IκBα promoters.","evidence":"ChIP, reporter assays, knockdown, flow cytometry, caspase-3 assays","pmids":["22754333","23054188"],"confidence":"Medium","gaps":["Single-laboratory studies","Whether p65/IκBα activation is direct in physiological settings unconfirmed"]},{"year":2013,"claim":"Uncovered DNA-methylation-based silencing by ZBTB7A through direct MBD3 interaction recruiting the Mi-2/NuRD-HDAC complex and BCoR-linked DNMTs/HP1 to CDKN1A, and revealed context-dependent tumor suppression via SOX9 antagonism.","evidence":"Co-IP, ChIP, methylated/non-methylated EMSA, reporter; conditional prostate Zbtb7a KO with target gene analysis","pmids":["23658227","23727861","23300578","23355454"],"confidence":"High","gaps":["Direct demonstration of DNMT-mediated methylation at the locus inferred from interactions","Reconciliation of oncogenic ARF-repression with tumor-suppressive senescence bypass left to context"]},{"year":2014,"claim":"Defined ZBTB7A as a direct transcriptional repressor of glycolysis (GLUT3, PFKP, PKM) whose loss elevates glycolytic flux, and revealed a non-transcriptional role regulating BCL-X splicing via SAM68.","evidence":"ChIP, reporter, metabolic assays, KO/KD cell and mouse models, TCGA analysis; co-IP, RIP, splicing assays, HDAC inhibitor","pmids":["25184678","24514149","25514493","24857950"],"confidence":"High","gaps":["Smad4 and ETS-1 interactions are single-laboratory (ETS-1 low confidence)","Mechanistic link between HDAC activity and splicing control incompletely defined"]},{"year":2015,"claim":"Tied loss of ZBTB7A DNA binding to malignancy, showing cancer-derived zinc-finger mutations abolish binding, de-repress glycolytic targets, and enhance proliferation, and that ZBTB7A represses MCAM to restrain metastasis.","evidence":"Zinc-finger mutagenesis, reporter and metabolic assays, genome database mining; ChIP, reporter, invasion assays, melanoma specimens","pmids":["26455326","25995384"],"confidence":"High","gaps":["Structural consequences of mutations not yet resolved at this stage","MCAM repression from single laboratory"]},{"year":2016,"claim":"Established ZBTB7A as a recurrently mutated gene in t(8;21) AML, with C-terminal zinc-finger mutations disrupting repressor and anti-proliferative activity, implying leukemogenic cooperation with RUNX1/RUNX1T1.","evidence":"Patient sequencing (23% of t(8;21) AML), reporter and proliferation assays of mutants","pmids":["27252013"],"confidence":"High","gaps":["Direct functional cooperation with RUNX1-RUNX1T1 not yet demonstrated experimentally at this point","Key downstream effector of the leukemic phenotype not pinpointed"]},{"year":2017,"claim":"Identified upstream regulation in erythroid cells (KLF1-driven expression of a novel transcript) and additional lineage-specific repressive targets, broadening the regulatory circuitry around ZBTB7A.","evidence":"ChIP, transcript analysis in erythroid differentiation; ChIP/reporter/RNA-IP in osteosarcoma (LINC00473)","pmids":["29296711","28942243"],"confidence":"Medium","gaps":["Functional consequence of the erythroid-specific transcript not fully defined","Single-laboratory target studies"]},{"year":2018,"claim":"Established ZBTB7A as a major direct repressor of fetal γ-globin via the -200 bp promoter element and, genome-wide, as a chromatin accessibility transducer required for NF-κB-driven inducible accessibility changes.","evidence":"CRISPR HPFH mutations, ChIP, EMSA, erythroid reporters; genome-wide ChIP-seq/ATAC-seq/RNA-seq with knockdown and p65 induction","pmids":["29610478","29813070","29764865"],"confidence":"High","gaps":["Mechanism by which ZBTB7A marks promoters for client-TF accessibility not molecularly resolved","HP1γ–ZBTB7A axis from single laboratory"]},{"year":2019,"claim":"Refined ZBTB7A's role in nuclear-receptor and metabolic circuits, showing AR-directed recruitment to E2F-Rb sites to suppress replication genes, reciprocal regulation with ERα/TRIM25, and hypoxic NF-κB repression de-repressing the MCT4 lactate exporter.","evidence":"ChIP-seq, RNA-seq, co-IP, xenografts; reporter, ubiquitination, ChIP, oligonucleotide pulldown assays","pmids":["31444154","30265334","31715186","31271899","30753838"],"confidence":"High","gaps":["Most signaling-loop studies from single laboratories","Integration of these loops into a unified regulatory logic incomplete"]},{"year":2020,"claim":"Demonstrated ZBTB7A's role in cell-fate chromatin remodeling during pluripotency transitions and functionally confirmed t(8;21) leukemic cooperativity, with WT ZBTB7A blocking RUNX1-RUNX1T1-driven clonal expansion through glycolysis-coupled cell-cycle arrest.","evidence":"ATAC-seq/ChIP-seq/RNA-seq in BMP4-driven PNT; lentiviral WT/mutant expression in CD34+ cells, Seahorse, cell cycle, 2-DG","pmids":["32393886","32115572"],"confidence":"High","gaps":["Dual opening/silencing activity during PNT mechanistically unexplained","Molecular link between glycolysis repression and cell-cycle arrest in leukemia not fully traced"]},{"year":2021,"claim":"Resolved the atomic basis of γ-globin repression, showing ZF1/ZF2 read the 5' C:G quadruplet and ZF4 the 3' quadruplet, and that the most disruptive HPFH mutations hit ZF1/ZF2-recognized bases.","evidence":"X-ray crystallography of the four-zinc-finger DBD bound to the -200 bp element plus mutant binding assays","pmids":["34592153"],"confidence":"High","gaps":["Structure of the full-length protein or POZ-mediated complexes on DNA not solved","Does not address corepressor recruitment geometry"]},{"year":2023,"claim":"Extended ZBTB7A's tumor-suppressive and metabolic repertoire to glioblastoma, showing direct repression of EPB41L5 (restraining EMT) and of HK2/LDHA (limiting glycolysis), with non-coding RNAs destabilizing ZBTB7A to release these programs.","evidence":"ChIP, RNA-seq, 3'UTR reporter, Seahorse, knockdown, in vivo tumor assays","pmids":["36596853","37066523","36243002"],"confidence":"Medium","gaps":["GBM target studies from single laboratories","Connection between oxidative-stress control in viral persistence and canonical transcription functions unclear"]},{"year":null,"claim":"How ZBTB7A integrates its opposing activator/repressor and oncogenic/tumor-suppressive outputs—and what determines whether it opens or silences chromatin at a given locus as an accessibility transducer—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for context-dependent activation vs repression","Molecular determinants of promoter selection for TF-induced accessibility unknown","Structure of POZ-corepressor complexes on chromatin not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,9,12,24,34,36]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,4,34,43]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,10,14,26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7,20]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,9,12,24,34,36]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9,11,12,37,42]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[24,29,46,42]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[20,36,41]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,26,37,38]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,30,42]}],"complexes":["Sin3A-HDAC corepressor complex","NCoR/SMRT corepressor complex","Mi-2/NuRD-HDAC complex (via MBD3)","ZBTB7A POZ-domain homodimer"],"partners":["SP1","RELA","AR","SMAD4","KHDRBS1","SOX9","MBD3","SREBF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95365","full_name":"Zinc finger and BTB domain-containing protein 7A","aliases":["Factor binding IST protein 1","FBI-1","Factor that binds to inducer of short transcripts protein 1","HIV-1 1st-binding protein 1","Leukemia/lymphoma-related factor","POZ and Krueppel erythroid myeloid ontogenic factor","POK erythroid myeloid ontogenic factor","Pokemon","Pokemon 1","TTF-I-interacting peptide 21","TIP21","Zinc finger protein 857A"],"length_aa":584,"mass_kda":61.4,"function":"Transcription factor that represses the transcription of a wide range of genes involved in cell proliferation and differentiation (PubMed:14701838, PubMed:17595526, PubMed:20812024, PubMed:25514493, PubMed:26455326, PubMed:26816381). Directly and specifically binds to the consensus sequence 5'-[GA][CA]GACCCCCCCCC-3' and represses transcription both by regulating the organization of chromatin and through the direct recruitment of transcription factors to gene regulatory regions (PubMed:12004059, PubMed:17595526, PubMed:20812024, PubMed:25514493, PubMed:26816381). Negatively regulates SMAD4 transcriptional activity in the TGF-beta signaling pathway through these two mechanisms (PubMed:25514493). That is, recruits the chromatin regulator HDAC1 to the SMAD4-DNA complex and in parallel prevents the recruitment of the transcriptional activators CREBBP and EP300 (PubMed:25514493). Collaborates with transcription factors like RELA to modify the accessibility of gene transcription regulatory regions to secondary transcription factors (By similarity). Also directly interacts with transcription factors like SP1 to prevent their binding to DNA (PubMed:12004059). Functions as an androgen receptor/AR transcriptional corepressor by recruiting NCOR1 and NCOR2 to the androgen response elements/ARE on target genes (PubMed:20812024). Thereby, negatively regulates androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024). Involved in the switch between fetal and adult globin expression during erythroid cells maturation (PubMed:26816381). Through its interaction with the NuRD complex regulates chromatin at the fetal globin genes to repress their transcription (PubMed:26816381). Specifically represses the transcription of the tumor suppressor ARF isoform from the CDKN2A gene (By similarity). Efficiently abrogates E2F1-dependent CDKN2A transactivation (By similarity). Regulates chondrogenesis through the transcriptional repression of specific genes via a mechanism that also requires histone deacetylation (By similarity). Regulates cell proliferation through the transcriptional regulation of genes involved in glycolysis (PubMed:26455326). Involved in adipogenesis through the regulation of genes involved in adipocyte differentiation (PubMed:14701838). Plays a key role in the differentiation of lymphoid progenitors into B and T lineages (By similarity). Promotes differentiation towards the B lineage by inhibiting the T-cell instructive Notch signaling pathway through the specific transcriptional repression of Notch downstream target genes (By similarity). Also regulates osteoclast differentiation (By similarity). May also play a role, independently of its transcriptional activity, in double-strand break repair via classical non-homologous end joining/cNHEJ (By similarity). Recruited to double-strand break sites on damage DNA, interacts with the DNA-dependent protein kinase complex and directly regulates its stability and activity in DNA repair (By similarity). May also modulate the splicing activity of KHDRBS1 toward BCL2L1 in a mechanism which is histone deacetylase-dependent and thereby negatively regulates the pro-apoptotic effect of KHDRBS1 (PubMed:24514149)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O95365/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZBTB7A","classification":"Not Classified","n_dependent_lines":287,"n_total_lines":1208,"dependency_fraction":0.23758278145695363},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZBTB7A","total_profiled":1310},"omim":[{"mim_id":"621229","title":"GATA2 ANTISENSE RNA 1, NONCODING; GATA2AS1","url":"https://www.omim.org/entry/621229"},{"mim_id":"619769","title":"MACROCEPHALY, NEURODEVELOPMENTAL DELAY, LYMPHOID HYPERPLASIA, AND PERSISTENT FETAL HEMOGLOBIN; 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Carcinoma.","date":"2018","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/29673422","citation_count":14,"is_preprint":false},{"pmid":"36596853","id":"PMC_36596853","title":"ZBTB7A suppresses glioblastoma tumorigenesis through the transcriptional repression of EPB41L5.","date":"2023","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36596853","citation_count":14,"is_preprint":false},{"pmid":"18364119","id":"PMC_18364119","title":"Expression of transcription factor Pokemon in non-small cell lung cancer and its clinical significance.","date":"2008","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18364119","citation_count":14,"is_preprint":false},{"pmid":"25875864","id":"PMC_25875864","title":"Resveratrol Represses Pokemon Expression in Human Glioma Cells.","date":"2015","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25875864","citation_count":14,"is_preprint":false},{"pmid":"34869045","id":"PMC_34869045","title":"Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34869045","citation_count":14,"is_preprint":false},{"pmid":"29207095","id":"PMC_29207095","title":"Upregulation of ZBTB7A exhibits a tumor suppressive role in gastric cancer cells.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29207095","citation_count":14,"is_preprint":false},{"pmid":"31715186","id":"PMC_31715186","title":"Knockdown of ZBTB7A inhibits cell proliferation of breast cancer through regulating the ubiquitination of estrogen receptor alpha.","date":"2019","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31715186","citation_count":14,"is_preprint":false},{"pmid":"31998789","id":"PMC_31998789","title":"Obesity-Induced Upregulation of ZBTB7A Promotes Lipid Accumulation through SREBP1.","date":"2020","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/31998789","citation_count":13,"is_preprint":false},{"pmid":"37066523","id":"PMC_37066523","title":"U3 snoRNA-mediated degradation of ZBTB7A regulates aerobic glycolysis in isocitrate dehydrogenase 1 wild-type glioblastoma cells.","date":"2023","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/37066523","citation_count":13,"is_preprint":false},{"pmid":"24175766","id":"PMC_24175766","title":"Expression of the proto-oncogene Pokemon in colorectal cancer--inhibitory effects of an siRNA.","date":"2013","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24175766","citation_count":13,"is_preprint":false},{"pmid":"36243002","id":"PMC_36243002","title":"ZBTB7A promotes virus-host homeostasis during human coronavirus 229E infection.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36243002","citation_count":13,"is_preprint":false},{"pmid":"25722217","id":"PMC_25722217","title":"Evaluation of transforming growth factor-β1 suppress Pokemon/epithelial-mesenchymal transition expression in human bladder cancer cells.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25722217","citation_count":13,"is_preprint":false},{"pmid":"35501800","id":"PMC_35501800","title":"ZBTB7A, a miR-144-3p targeted gene, accelerates bladder cancer progression via downregulating HIC1 expression.","date":"2022","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/35501800","citation_count":12,"is_preprint":false},{"pmid":"30941230","id":"PMC_30941230","title":"Pokemon Inhibits Transforming Growth Factor β-Smad4-Related Cell Proliferation Arrest in Breast Cancer through Specificity Protein 1.","date":"2019","source":"Journal of breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30941230","citation_count":12,"is_preprint":false},{"pmid":"32965543","id":"PMC_32965543","title":"Elevated ZBTB7A expression in the tumor invasive front correlates with more tumor budding formation in gastric adenocarcinoma.","date":"2020","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32965543","citation_count":12,"is_preprint":false},{"pmid":"31205540","id":"PMC_31205540","title":"Pro-oncogene Pokemon Promotes Prostate Cancer Progression by Inducing STRN4 Expression.","date":"2019","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31205540","citation_count":12,"is_preprint":false},{"pmid":"34304709","id":"PMC_34304709","title":"Krüppel-like factor 1 (KLF1) promoted the proliferation, migration and invasion of human lens epithelial cells by enhancing the expression of Zinc Finger and BTB Domain Containing 7A (ZBTB7A) and activating Wnt/β-catenin pathway.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34304709","citation_count":12,"is_preprint":false},{"pmid":"21771706","id":"PMC_21771706","title":"Pokemon reduces Bcl-2 expression through NF-κ Bp65: A possible mechanism of hepatocellular carcinoma.","date":"2011","source":"Asian Pacific journal of tropical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21771706","citation_count":12,"is_preprint":false},{"pmid":"24393848","id":"PMC_24393848","title":"The effect of Pokemon on bladder cancer epithelial-mesenchymal transition.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24393848","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48950,"output_tokens":11297,"usd":0.158153,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22473,"output_tokens":7619,"usd":0.15142,"stage2_stop_reason":"end_turn"},"total_usd":0.309573,"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\": 1997,\n      \"finding\": \"FBI-1 (ZBTB7A) was purified as a cellular factor that specifically binds to the HIV-1 inducer of short transcripts (IST), a bipartite DNA element downstream of the HIV-1 transcriptional start site; binding of FBI-1 to IST correlates with the ability of IST mutants to direct abortive (short) transcript synthesis, suggesting FBI-1 promotes transcription elongation blocks.\",\n      \"method\": \"Biochemical purification, specific protein-DNA crosslinking, EMSA with IST mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical purification, crosslinking, and functional correlation with IST mutants in a single rigorous study\",\n      \"pmids\": [\"9199312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FBI-1 (ZBTB7A) contains an N-terminal POZ/BTB domain and four C-terminal Krüppel-type zinc fingers; the C-terminus is sufficient for specific DNA binding, and FBI-1 forms homomers through its POZ domain (and in vivo through its zinc finger domain); FBI-1 also physically associates with HIV-1 Tat protein.\",\n      \"method\": \"cDNA cloning, domain deletion analysis, in vivo homomer detection, co-immunoprecipitation with Tat\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — cloning plus domain mapping plus co-IP, multiple orthogonal methods in one study, replicated in subsequent literature\",\n      \"pmids\": [\"9973611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The POZ domain of FBI-1 (ZBTB7A) directly interacts with the zinc finger DNA-binding domain of Sp1, preventing Sp1 from binding GC boxes on the ADH5/FDH promoter, thereby repressing transcription; this mechanism was shared by the POZ domains of PLZF and BCL-6.\",\n      \"method\": \"GST pull-down (POZ domain fusions), EMSA, DNase I footprinting, ChIP, Gal4 fusion reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution (GST pull-down, DNase I footprinting), ChIP, and reporter assay providing multiple orthogonal lines of evidence\",\n      \"pmids\": [\"12004059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FBI-1 stimulates HIV-1 Tat-activated transcription; this effect requires the same FBI-1 domain that mediates physical Tat–FBI-1 association in vivo. FBI-1 partially co-localizes with Tat and P-TEFb (Cdk9/CyclinT1) at nuclear speckles, and its nuclear distribution depends on its DNA-binding domain, cellular DNA, and active transcription.\",\n      \"method\": \"Transcription reporter assay, co-immunoprecipitation, confocal microscopy/immunofluorescence co-localization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reporter assay plus co-IP plus localization, but single laboratory\",\n      \"pmids\": [\"11907272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FBI-1 (ZBTB7A) binds to inverted, direct, and everted sequence repeats with the consensus G(A/G)GGG(T/C)(C/T)(T/C)(C/T) with high flexibility in orientation and spacing, indicating highly flexible DNA recognition by a POZ-domain protein.\",\n      \"method\": \"EMSA with multiple viral and cellular binding sites, sequence analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic EMSA across multiple binding sites, single laboratory\",\n      \"pmids\": [\"12750370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FBI-1 (ZBTB7A) is induced during early human and murine preadipocyte differentiation and promotes adipogenesis; stably overexpressing FBI-1 in 3T3-L1 cells accelerated differentiation markers and lipid accumulation while reducing DNA synthesis and cyclin A expression, placing FBI-1 as a dual regulator switching cells from proliferation to differentiation.\",\n      \"method\": \"Stable cell line overexpression, quantification of differentiation markers, lipid accumulation assay, cell proliferation assay, cyclin A protein measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — overexpression gain-of-function with defined cellular phenotypes, single laboratory\",\n      \"pmids\": [\"14701838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Pokemon/ZBTB7A directly represses ARF tumor suppressor gene transcription through direct promoter binding; mouse embryonic fibroblasts lacking Zbtb7 are completely refractory to oncogene-mediated transformation, and Pokemon overexpression causes oncogenic transformation in vitro and in transgenic mice.\",\n      \"method\": \"ChIP, promoter reporter assay, MEF transformation assay, Zbtb7 knockout MEFs, transgenic mouse model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct promoter binding (ChIP), loss-of-function (KO MEFs), gain-of-function (transgenic mice), multiple orthogonal methods, replicated by multiple subsequent studies\",\n      \"pmids\": [\"15662416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FBI-1 (ZBTB7A) interacts with the Rel homology domain of NF-κB p65 via its POZ domain in vivo and in vitro, enhances NF-κB-mediated E-selectin gene transcription, promotes nuclear localization and stability of p65, and also interacts with IκBα and IκBβ.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro protein-protein interaction), luciferase reporter assay, confocal microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus reporter assay plus imaging, single laboratory\",\n      \"pmids\": [\"15917220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The BTB/POZ domain of human LRF/ZBTB7A adopts the canonical BTB homodimer fold; the lateral groove and charged pocket on the homodimer surface differ substantially from BCL6 BTB, and the 17-residue BCL6 Binding Domain (BBD) of SMRT co-repressor does not bind to the LRF BTB domain.\",\n      \"method\": \"X-ray crystallography (2.1 Å), in vitro binding assay (BBD peptide binding test)\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.1 Å with functional validation (negative binding result for SMRT BBD), single but rigorous study\",\n      \"pmids\": [\"17189472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FBI-1 (ZBTB7A) represses Rb gene transcription by binding to four GC-rich FBI-1-response elements (FREs) in the Rb promoter and by competing with Sp1 at GC-box 2 and FRE3; repression involves recruitment of a co-repressor–HDAC complex through the POZ domain, leading to deacetylation of H3 and H4 histones at the Rb promoter. FBI-1 also inhibits C2C12 myoblast differentiation by repressing Rb.\",\n      \"method\": \"ChIP, EMSA, luciferase reporter assay, site-directed mutagenesis, histone deacetylation assay, myoblast differentiation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP plus EMSA plus mutagenesis plus functional differentiation assay, multiple orthogonal methods\",\n      \"pmids\": [\"18801742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FBI-1 (ZBTB7A) and SREBP-1 interact directly via their DNA-binding domains and synergistically activate FASN gene transcription; FBI-1 alters the binding pattern of Sp1 and SREBP-1 on GC-box and SRE/E-box elements to drive higher Sp1 binding to the proximal FASN promoter.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, ChIP, EMSA, co-transfection experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus reporter assay, single laboratory\",\n      \"pmids\": [\"18682402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FBI-1 (ZBTB7A) acts as a dual regulator in adipogenesis: it represses cyclin A through an indirect mechanism (inhibiting Sp1 binding at the cyclin A promoter) and represses E2F-4 directly via a FBI-1 binding element; FBI-1 binds Sin3A and HDAC-1 to form a repressor complex through its POZ domain.\",\n      \"method\": \"Luciferase reporter assay, EMSA, co-immunoprecipitation, site-directed mutagenesis, POZ domain deletion mutants\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, EMSA, mutagenesis, reporter assay, single laboratory\",\n      \"pmids\": [\"18368381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FBI-1 (ZBTB7A) represses p21CIP1 transcription by direct binding to the proximal Sp1-3 GC-box and distal p53-responsive elements, competing with both Sp1 and p53; it also recruits co-repressors mSin3A, NCoR, and SMRT, leading to deacetylation of Ac-H3 and Ac-H4 histones at the p21 promoter. FBI-1 functions as a master controller of the ARF–Hdm2–p53–p21 pathway.\",\n      \"method\": \"ChIP, EMSA, luciferase reporter assay, co-immunoprecipitation, histone deacetylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, EMSA, co-IP, mutagenesis), consistent with prior findings on FBI-1 repressor mechanism\",\n      \"pmids\": [\"19244234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"eEF1A/CCS-3 directly interacts with FBI-1 (ZBTB7A) through both the zinc finger and POZ domains of FBI-1; CCS-3 enhances FBI-1-mediated transcriptional repression of p21CIP1 by facilitating interaction with co-repressors SMRT and BCoR at the POZ domain.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, MALDI-TOF mass spectrometry, immunofluorescence co-localization, luciferase reporter assay\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pull-down plus co-IP plus reporter assay, single laboratory\",\n      \"pmids\": [\"19471103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FBI-1 (ZBTB7A) acts as a co-repressor of the androgen receptor (AR) in prostate cancer cells; FBI-1 physically interacts with AR in a ligand-dependent manner and forms a ternary complex with AR and SMRT, enhancing recruitment of NCoR and SMRT to endogenous PSA upstream sequences. FBI-1-mediated inhibition of AR transcriptional activity is partially dependent on HDAC activity.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, luciferase reporter assay, HDAC inhibitor treatment\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus reporter assay, single laboratory\",\n      \"pmids\": [\"20812024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZBTB7A/LRF (FBI-1/OCZF) is expressed in osteoclasts, is upregulated by RANKL in primary macrophages, and is required for RANKL-induced osteoclast formation in vitro; transgenic mice overexpressing OCZF under the cathepsin K promoter show decreased bone volume, increased osteoclast number, and promoted osteoclast survival.\",\n      \"method\": \"Immunostaining, in situ hybridization, transgenic mouse model (OCZF-Tg), siRNA knockdown of LRF in osteoclast differentiation assay, bone histomorphometry, pQCT\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse model plus in vitro knockdown plus histomorphometry, multiple independent methods\",\n      \"pmids\": [\"21590684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Pokemon/ZBTB7A directly binds GT boxes in the survivin promoter and induces survivin expression in breast cancer cells; ChIP and site-directed mutagenesis confirmed direct promoter binding.\",\n      \"method\": \"ChIP, site-directed mutagenesis, DNA microarray, luciferase reporter\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus mutagenesis plus microarray, single laboratory\",\n      \"pmids\": [\"21392388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FBI-1 (ZBTB7A) directly activates MT1-MMP promoter transcription by binding the ~600 bp 5'-flanking sequence of MT1-MMP (confirmed by promoter reporter assay and ChIP), leading to enhanced cancer cell migration and invasion; MT1-MMP knockdown abolished FBI-1-mediated invasion.\",\n      \"method\": \"ChIP, promoter reporter assay (promoter deletion constructs), siRNA knockdown of MT1-MMP, invasion/migration assay\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus epistasis (MT1-MMP KD rescues phenotype), single laboratory\",\n      \"pmids\": [\"21176152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Pokemon/ZBTB7A directly binds the Bim promoter and suppresses Bim transcription, rendering liver cells resistant to anoikis; Pokemon knockdown enhances sensitivity to anoikis and chemical apoptotic stress, while ectopic Pokemon expression confers anoikis resistance.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP, siRNA knockdown, flow cytometry, caspase-3 activity assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus gain/loss-of-function, single laboratory\",\n      \"pmids\": [\"22754333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Pokemon/ZBTB7A directly binds the p65 promoter element at -434 to -430 bp and the IκBα promoter element at -453 to -448 bp, activating transcription of both, revealing a homeostatic regulatory role in NF-κB signaling.\",\n      \"method\": \"ChIP, targeted mutagenesis, luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus mutagenesis plus reporter assay, single laboratory\",\n      \"pmids\": [\"23054188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FBI-1 (ZBTB7A) directly interacts with MBD3 in the nucleus; through MBD3, FBI-1 recruits the Mi-2/NuRD-HDAC complex to the CDKN1A promoter for epigenetic repression; MBD3 modulates FBI-1 interactions with co-repressors (decreasing NCoR/SMRT interaction, increasing BCoR interaction); BCoR links to DNMTs and HP1, enabling DNA methylation-based silencing of p21WAF/CDKN1A.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, EMSA (methylated and non-methylated DNA binding), luciferase reporter assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-IP plus ChIP plus EMSA plus reporter assay, multiple orthogonal methods revealing epigenetic mechanism\",\n      \"pmids\": [\"23658227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ZBTB7A physically interacts with SOX9 and functionally antagonizes SOX9 transcriptional activity on target genes MIA (tumor invasion) and H19 (lncRNA precursor for RB-targeting miRNA); prostate-specific Zbtb7a inactivation accelerates Pten loss-driven tumorigenesis through bypass of Pten loss-induced cellular senescence, Rb downregulation, and invasive cancer.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction), conditional knockout mouse model (prostate-specific), RT-PCR/Western blot of target gene expression, histopathological analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-IP plus conditional KO mouse model plus target gene analysis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23727861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Pokemon/ZBTB7A silencing in HCC inhibits the PI3K/Akt and c-Raf/MEK/ERK pathways and modulates cell cycle regulators, suppressing cell proliferation and migration in vitro and tumor growth in xenograft mice.\",\n      \"method\": \"Stable shRNA knockdown, Western blot (pathway markers), cell proliferation and migration assays, xenograft mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — stable KD plus pathway marker analysis plus in vivo model, single laboratory\",\n      \"pmids\": [\"23300578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Pokemon/ZBTB7A directly binds the miR-21 promoter at GC boxes (-684 to -679 bp and -652 to -647 bp) and upregulates miR-21 transcription, which in turn suppresses Sprouty1 (a miR-21 target); site-directed mutagenesis of GC boxes abolished Pokemon regulation of miR-21.\",\n      \"method\": \"ChIP, luciferase reporter assay, site-directed mutagenesis, siRNA\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus mutagenesis plus reporter assay, single laboratory\",\n      \"pmids\": [\"23355454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZBTB7A directly binds to the promoters of key glycolytic genes GLUT3, PFKP, and PKM and transcriptionally represses them; ZBTB7A-deficient tumors exhibit elevated glycolysis and heightened sensitivity to glycolysis inhibition.\",\n      \"method\": \"ChIP, luciferase reporter assay, metabolic assays, ZBTB7A loss-of-function (KO/KD) in cell lines and mouse models, TCGA data analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct ChIP plus reporter assay plus metabolic functional readout plus in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"25184678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FBI-1 (ZBTB7A) interacts with the splicing factor SAM68 and reduces SAM68 binding to BCL-X mRNA, shifting BCL-X alternative splicing toward the anti-apoptotic BCL-XL variant and counteracting SAM68-mediated apoptosis; this splicing role requires HDAC activity.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, RT-PCR splicing assay, FBI-1 knockdown, SAM68 interaction-domain mutant, HDAC inhibitor treatment\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-IP plus RIP plus splicing assay plus domain mutant plus pharmacological validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24514149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Pokemon/ZBTB7A directly interacts with Smad4, and this interaction is enhanced by TGF-β1 treatment; Pokemon overexpression decreases TGF-β-induced transcriptional activities by recruiting HDAC1 to the Smad4 complex and reducing Smad4–p300/CBP interaction, without affecting Smad2/3 activation or Smad complex formation.\",\n      \"method\": \"Co-immunoprecipitation (in vitro and in vivo), luciferase reporter assay, ChIP (Pokemon recruitment to Smad4-DNA complex), Western blot\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus reporter assay, single laboratory\",\n      \"pmids\": [\"25514493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FBI-1 (ZBTB7A) physically interacts with ETS-1, promotes ETS-1 nuclear accumulation, and enhances ETS-1 recruitment to target gene promoters; this occurs partly by FBI-1 downregulating p53-mediated inhibition of ETS-1.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, luciferase reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP plus ChIP, single laboratory, limited mechanistic follow-up\",\n      \"pmids\": [\"24857950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZBTB7A directly binds the MCAM promoter and transcriptionally represses MCAM expression; loss of ZBTB7A leads to upregulation of MCAM and enhanced melanoma cell invasion and metastasis.\",\n      \"method\": \"ChIP, promoter reporter assay, loss-of-function (ZBTB7A KD), invasion/metastasis assays, human melanoma specimen analysis\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus functional invasion assay, single laboratory\",\n      \"pmids\": [\"25995384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Zinc finger domain mutations in ZBTB7A (identified in human cancers) result in loss of DNA-binding function; cells harboring these mutations show marked upregulation of glycolytic target genes (GLUT3, PFKP, PKM), increased glycolysis, and enhanced proliferation.\",\n      \"method\": \"Site-directed mutagenesis of zinc finger domain, luciferase reporter assay, metabolic assays, cell proliferation assay, cancer genome database mining\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus reporter assay plus metabolic functional readout, single laboratory but rigorous functional characterization\",\n      \"pmids\": [\"26455326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Recurrent ZBTB7A mutations (missense and truncating) affecting the C-terminal zinc-finger domain occur in 23% of AML t(8;21) patients; these mutations disrupt the transcriptional repressor activity and anti-proliferative effect of ZBTB7A, and their specific association with t(8;21) AML indicates leukaemogenic cooperativity with RUNX1/RUNX1T1.\",\n      \"method\": \"Sequencing of patient samples, functional luciferase reporter assay (repressor activity), proliferation assay of mutant ZBTB7A-expressing cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — patient-derived mutations functionally validated in reporter assay and proliferation assay, replicated across 56 patients\",\n      \"pmids\": [\"27252013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLF1 directly drives ZBTB7A expression in erythroid cells by binding to the ZBTB7A proximal promoter (confirmed by ChIP); an erythroid-specific regulatory mechanism upregulates a novel ZBTB7A transcript in the erythroid compartment.\",\n      \"method\": \"ChIP, promoter analysis, RT-PCR of novel transcript, erythroid cell differentiation system\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus transcript analysis, single laboratory\",\n      \"pmids\": [\"29296711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZBTB7A directly binds the LINC00473 promoter and transcriptionally represses LINC00473 expression in osteosarcoma; LINC00473 interacts with transcription factor C/EBPβ, facilitating its binding to the IL24 promoter to decrease chemoresistance.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown, RNA immunoprecipitation\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus RNA-IP, single laboratory\",\n      \"pmids\": [\"28942243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Zbtb7a induction in alveolar macrophages (AMs) is a critical early event in DSA-induced chronic lung allograft rejection; selective disruption of Zbtb7a in AMs reduced bronchiolar occlusion and immune responses to lung-restricted self-antigens; antigen presentation by AMs is Zbtb7a-dependent, as Zbtb7a-deficient AMs failed to induce antibody and T cell responses.\",\n      \"method\": \"Conditional macrophage-specific Zbtb7a knockout, murine obliterative airway disease model, adoptive transfer, immunological readouts (antibody and T cell responses)\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO plus in vivo model plus mechanistic immune readouts, replicated in mouse and human correlation\",\n      \"pmids\": [\"28701473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZBTB7A directly binds the γ-globin gene promoter at the -200 bp region (containing two copies of four consecutive C:G base pairs) and acts as a major direct repressor of fetal HBG1/HBG2 (γ-globin) gene expression; naturally occurring HPFH-associated point mutations at -200 bp disrupt ZBTB7A binding and elevate γ-globin expression.\",\n      \"method\": \"CRISPR-Cas9 introduction of HPFH mutations, ChIP, EMSA, erythroid cell reporter assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR functional mutation plus ChIP plus EMSA, multiple orthogonal methods, replicated in structural study (PMID 34592153)\",\n      \"pmids\": [\"29610478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HP1γ (CBX3) directly represses ZBTB7A expression in lung adenocarcinoma cells; knockdown of ZBTB7A significantly restores the proliferation, colony formation, and migration defects caused by HP1γ depletion, placing ZBTB7A downstream of HP1γ in a lung adenocarcinoma-promoting pathway; ZBTB7A in turn downregulates AXL expression.\",\n      \"method\": \"siRNA knockdown (HP1γ and ZBTB7A), epistasis rescue experiment, ChIP (HP1γ on ZBTB7A locus), cell proliferation/colony/migration assays, in vivo K-RasG12D mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue plus ChIP plus in vivo model, single laboratory\",\n      \"pmids\": [\"29764865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Zbtb7a binds to a significant fraction of genomic promoters and enhancers genome-wide; it is required for inducible changes in chromatin accessibility driven by NF-κB p65 and other transcription factors (TFs); Zbtb7a associates with promoters independently of client TF binding and specifies promoters amenable to TF-induced accessibility changes, acting as an accessibility transducer.\",\n      \"method\": \"ChIP-seq, ATAC-seq, RNA-seq, Zbtb7a knockdown, p65 induction experiments in macrophages\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide ChIP-seq plus ATAC-seq plus RNA-seq plus functional KD, multiple orthogonal genome-scale methods\",\n      \"pmids\": [\"29813070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZBTB7A mediates AR-dependent transcriptional repression in prostate cancer cells; ZBTB7A is recruited to E2F-Rb binding sites by AR and negatively regulates E2F1 transcriptional activity on DNA replication genes; AR recruitment of Rb strengthens the E2F-Rb repression complex; ZBTB7A suppresses castration-resistant prostate cancer growth in vitro and in vivo.\",\n      \"method\": \"ChIP-seq, RNA-seq, siRNA knockdown, co-immunoprecipitation, in vitro and xenograft in vivo assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP-seq plus RNA-seq plus co-IP plus functional in vivo model, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31444154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Under hypoxia, NF-κB (RelA/p65) binds NF-κB-binding elements in the ZBTB7A promoter and represses ZBTB7A expression, thereby de-repressing SLC16A3 (MCT4); FBI-1/ZBTB7A directly represses SLC16A3 by binding both FREs and HREs in the SLC16A3 promoter during normoxia.\",\n      \"method\": \"Transient transfection/reporter assay of SLC16A3 and ZBTB7A promoter constructs, oligonucleotide pulldown, ChIP\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus oligonucleotide pulldown, single laboratory\",\n      \"pmids\": [\"31271899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZBTB7A transcriptionally regulates ERα (ESR1) expression in ERα-positive breast cancer by binding the ESR1 promoter (+146 to +461 bp downstream of TSS), and inhibition of ZBTB7A upregulates E3 ligase TRIM25, enhancing ERα ubiquitination and proteasomal degradation; ERα in turn potentiates ZBTB7A expression post-translationally, forming a positive feedback loop.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown, TRIM25 co-IP/ubiquitination assay, estrogen-response element reporter\",\n      \"journal\": \"Journal of molecular cell biology / Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus ubiquitination assay, single laboratory\",\n      \"pmids\": [\"30265334\", \"31715186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZBTB7A directly binds the LncRNA GAS5 promoter and transcriptionally suppresses GAS5 expression in osteosarcoma cells, reducing ER stress-induced apoptosis; miR-663a (induced by ER stress) directly targets the 3'UTR of ZBTB7A to downregulate it.\",\n      \"method\": \"ChIP, luciferase reporter assay, miRNA 3'UTR reporter assay, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus functional in vivo readout, single laboratory\",\n      \"pmids\": [\"30753838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BMP4 signaling opens chromatin at Zbtb7a/b loci early during primed-to-naive pluripotency transition (PNT); ZBTB7A in turn occupies and facilitates opening of naive pluripotent chromatin loci (activating nearby genes) while also occupying loci that are silenced, consistent with dual roles in chromatin remodeling during PNT.\",\n      \"method\": \"ATAC-seq (chromatin accessibility), ChIP-seq (ZBTB7A binding), RNA-seq, BMP4-driven PNT system, ZBTB7A overexpression/knockdown\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ATAC-seq plus ChIP-seq plus RNA-seq plus gain/loss-of-function in a defined differentiation system\",\n      \"pmids\": [\"32393886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wild-type ZBTB7A prevents RUNX1-RUNX1T1 (AML1-ETO)-mediated clonal expansion of human CD34+ hematopoietic stem and progenitor cells; ZBTB7A mutations enable this clonal expansion. ZBTB7A loss increases glycolysis and sensitizes t(8;21) leukemic blasts to 2-deoxy-D-glucose. ZBTB7A expression in t(8;21) cells causes cell cycle arrest recapitulated by glycolysis inhibition.\",\n      \"method\": \"Lentiviral expression of WT/mutant ZBTB7A in CD34+ cells, clonal expansion assay, Seahorse metabolic assay, cell cycle analysis, 2-DG treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — primary human CD34+ cell model plus metabolic assays plus cell cycle analysis, multiple orthogonal methods\",\n      \"pmids\": [\"32115572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"X-ray crystal structures of the ZBTB7A DNA-binding domain (four zinc fingers) in complex with the γ-globin promoter -200 bp element reveal that ZF1 and ZF2 recognize the 5' C:G quadruple and ZF4 contacts the 3' C:G quadruple; HPFH-associated mutations that impair ZBTB7A binding most severely disrupt base pairs recognized by ZF1 and ZF2.\",\n      \"method\": \"X-ray crystallography, in vitro DNA-binding assays with HPFH mutant sequences\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus functional binding assays with disease-relevant mutations, highly rigorous single study\",\n      \"pmids\": [\"34592153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR activation screen identified ZBTB7A as a factor that, when upregulated, promotes cell survival and allows HCoV-229E to establish a persistent homeostatic infection rather than causing cell death; control of oxidative stress is a primary driver of cellular survival during HCoV-229E infection downstream of ZBTB7A.\",\n      \"method\": \"CRISPR activation screen, viral infection assay (HCoV-229E), cell viability assay, oxidative stress measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus functional viral infection validation, single laboratory\",\n      \"pmids\": [\"36243002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZBTB7A directly binds the EPB41L5 gene promoter and represses its transcription in glioblastoma cells; ZBTB7A depletion induces GBM progression and metastasis, while ZBTB7A expression dramatically inhibits GBM tumor growth by suppressing EPB41L5-driven EMT.\",\n      \"method\": \"RNA-seq (ZBTB7A-depleted vs. control), ChIP (ZBTB7A binding to EPB41L5 promoter), loss-of-function (siRNA/shRNA), in vitro invasion assay, in vivo tumor growth assay\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus RNA-seq plus functional in vivo assay, single laboratory\",\n      \"pmids\": [\"36596853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZBTB7A directly binds the promoter regions of HK2 and LDHA, transcriptionally inhibiting their expression; small nucleolar RNA-derived fragment U3-miR reduces ZBTB7A mRNA stability (via ZBTB7A 3'UTR binding), thereby releasing HK2/LDHA repression and enhancing aerobic glycolysis in IDH1-wild-type glioblastoma cells.\",\n      \"method\": \"ChIP (ZBTB7A on HK2 and LDHA promoters), luciferase 3'UTR reporter assay, Seahorse glycolysis assay, siRNA knockdown\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus metabolic functional assay, single laboratory\",\n      \"pmids\": [\"37066523\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZBTB7A (FBI-1/LRF/Pokemon) is a BTB-zinc finger transcriptional repressor that homodimerizes through its POZ/BTB domain, binds GC-rich DNA elements via four C-terminal zinc fingers, and represses a broad set of target genes (ARF, RB, p21/CDKN1A, glycolytic enzymes GLUT3/PFKP/PKM/HK2/LDHA, MCAM, fetal γ-globin/HBG, MT1-MMP, BCL-2 family members, and others) by recruiting co-repressor–HDAC complexes (NCoR, SMRT, BCoR, Sin3A, Mi-2/NuRD) and promoting histone deacetylation and, in some contexts, DNA methylation; it also regulates alternative splicing of BCL-X by interacting with SAM68, modulates NF-κB and AR signaling through direct protein–protein interactions, controls chromatin accessibility at promoters/enhancers genome-wide as an accessibility transducer for multiple transcription factors, acts as a direct repressor of fetal globin genes (binding the γ-globin -200 bp promoter element through ZF1/ZF2/ZF4) whose structural basis has been resolved crystallographically, and has context-dependent oncogenic or tumor-suppressive roles depending on cancer type and interacting genetic lesions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZBTB7A (FBI-1/LRF/Pokemon) is a sequence-specific BTB-zinc finger transcription factor that controls cell proliferation, differentiation, metabolism, and lineage-specific gene programs, acting predominantly as a transcriptional repressor while also functioning as a genome-wide chromatin accessibility transducer [#6, #24, #36]. It is built from an N-terminal POZ/BTB domain that mediates homodimerization and a C-terminal array of four Krüppel-type zinc fingers that confer specific binding to GC-rich elements with flexible orientation and spacing [#1, #4]. Through its POZ domain it recruits corepressor–HDAC machinery (Sin3A/HDAC1, NCoR, SMRT, BCoR) to silence target promoters, drive histone H3/H4 deacetylation, and—via MBD3-dependent recruitment of the Mi-2/NuRD complex linked to DNMTs and HP1—impose DNA-methylation-based silencing [#9, #11, #12, #20]. The same POZ surface also directly competes with or sequesters other DNA-binding factors, including Sp1 at GC boxes, p53 at responsive elements, and SOX9, redirecting promoter occupancy [#2, #12, #21]. Through this repertoire ZBTB7A represses cell-cycle and tumor-suppressor genes including ARF, Rb, and p21/CDKN1A, positioning it as a controller of the ARF–p53–p21 axis whose overexpression transforms cells and whose loss bypasses senescence [#6, #9, #12, #21]. ZBTB7A is a master repressor of glycolysis, binding and silencing GLUT3, PFKP, PKM, HK2, and LDHA, such that loss-of-function elevates aerobic glycolysis and sensitizes tumors to glycolytic inhibition [#24, #29, #46]. In erythroid cells it is induced by KLF1 and directly represses fetal γ-globin (HBG1/HBG2) by binding two C:G quadruplets in the -200 bp promoter through ZF1, ZF2, and ZF4, a recognition mode resolved crystallographically and disrupted by HPFH point mutations [#31, #34, #43]. Beyond classical repression, ZBTB7A modulates partner transcription factors and signaling through direct protein–protein interactions with NF-κB p65, the androgen receptor, Smad4, ETS-1, and SREBP-1, and regulates BCL-X alternative splicing by interacting with SAM68 [#7, #10, #14, #25, #26, #37]. Recurrent zinc-finger mutations that abolish DNA binding occur in t(8;21) AML and cooperate with RUNX1-RUNX1T1 to permit clonal expansion of hematopoietic progenitors, while context-dependent roles render ZBTB7A oncogenic or tumor-suppressive across cancer types [#29, #30, #42].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established ZBTB7A as a sequence-specific DNA-binding factor by identifying it as the cellular protein recognizing the HIV-1 IST element and linking its binding to transcriptional elongation control.\",\n      \"evidence\": \"Biochemical purification, protein-DNA crosslinking, and EMSA with IST mutants\",\n      \"pmids\": [\"9199312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the protein's domain architecture\", \"Cellular target genes beyond the viral element unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the bipartite architecture—N-terminal POZ/BTB domain mediating homomerization and four C-terminal zinc fingers sufficient for DNA binding—and showed physical association with HIV-1 Tat.\",\n      \"evidence\": \"cDNA cloning, domain deletion analysis, in vivo homomer detection, co-IP with Tat\",\n      \"pmids\": [\"9973611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular corepressor partners not yet identified\", \"DNA consensus not yet systematically defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Revealed a non-canonical repression mode in which the POZ domain directly binds the Sp1 DNA-binding domain to evict Sp1 from GC boxes, establishing competitive repression independent of ZBTB7A's own DNA binding.\",\n      \"evidence\": \"GST pull-down, EMSA, DNase I footprinting, ChIP, and Gal4 reporter assay on ADH5/FDH promoter\",\n      \"pmids\": [\"12004059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of Sp1 competition across promoters untested at the time\", \"HDAC recruitment not yet shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Characterized the flexible GC-rich consensus ZBTB7A recognizes and showed its induction promotes adipocyte differentiation while suppressing proliferation, framing it as a proliferation-to-differentiation switch.\",\n      \"evidence\": \"EMSA across binding sites; overexpression in 3T3-L1 with differentiation, lipid, and proliferation readouts\",\n      \"pmids\": [\"12750370\", \"14701838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adipogenesis data are overexpression gain-of-function\", \"Direct target genes driving the differentiation switch not fully mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined ZBTB7A as a bona fide proto-oncogene by showing direct ARF repression, that its loss renders fibroblasts refractory to transformation, and that overexpression transforms cells and mice.\",\n      \"evidence\": \"ChIP, reporter assay, Zbtb7 KO MEF transformation assay, transgenic mouse model\",\n      \"pmids\": [\"15662416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the context-dependence (oncogene vs tumor suppressor) seen in later studies\", \"Corepressor complex composition at ARF not detailed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed ZBTB7A also engages signaling transcription factors directly, binding NF-κB p65 via its POZ domain to enhance p65 stability and target gene transcription.\",\n      \"evidence\": \"Reciprocal co-IP, luciferase reporter, confocal microscopy\",\n      \"pmids\": [\"15917220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-laboratory interaction data\", \"Whether p65 regulation is direct transcriptional or purely stability-based not fully separated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the structural basis of POZ/BTB homodimerization and demonstrated that the LRF BTB surface diverges from BCL6, explaining why the SMRT BCL6-binding peptide does not engage it.\",\n      \"evidence\": \"X-ray crystallography at 2.1 Å plus BBD peptide binding assay\",\n      \"pmids\": [\"17189472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the actual corepressor-recruitment surface used by LRF\", \"No DNA-bound structure\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mechanistically linked ZBTB7A repression to corepressor-HDAC recruitment, showing Rb, p21, cyclin A, and E2F-4 silencing through POZ-mediated Sin3A/HDAC1 binding, histone deacetylation, and Sp1 competition.\",\n      \"evidence\": \"ChIP, EMSA, reporter assays, mutagenesis, histone deacetylation and differentiation assays\",\n      \"pmids\": [\"18801742\", \"18368381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinction between direct binding and Sp1 competition at each target not always resolved\", \"In vivo relevance to differentiation tested only in cell models\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated context-dependent transcriptional activation, with ZBTB7A directly partnering SREBP-1 to synergistically activate FASN by remodeling Sp1/SREBP-1 promoter occupancy.\",\n      \"evidence\": \"Co-IP, ChIP, EMSA, reporter and co-transfection assays\",\n      \"pmids\": [\"18682402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-laboratory finding\", \"How the repressor switches to a coactivator mode mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Positioned ZBTB7A as a master controller of the ARF–Hdm2–p53–p21 axis through direct p21 repression involving competition with both Sp1 and p53 and recruitment of mSin3A/NCoR/SMRT.\",\n      \"evidence\": \"ChIP, EMSA, reporter assays, co-IP, histone deacetylation assay; plus eEF1A/CCS-3 corepressor-bridging study\",\n      \"pmids\": [\"19244234\", \"19471103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CCS-3 bridging interaction not independently replicated\", \"Relative contribution of Sp1 vs p53 competition not quantified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended ZBTB7A's interactome to nuclear receptors, showing ligand-dependent corepression of the androgen receptor via a ternary AR–ZBTB7A–SMRT complex and HDAC-dependent inhibition.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assays, HDAC inhibitor treatment in prostate cancer cells\",\n      \"pmids\": [\"20812024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-laboratory interaction data\", \"Endogenous target gene scope limited to PSA\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified tissue-specific roles in bone and demonstrated activating as well as repressive functions in cancer, showing requirement for RANKL-induced osteoclastogenesis and direct activation of survivin and MT1-MMP to promote invasion.\",\n      \"evidence\": \"Transgenic mouse, siRNA knockdown, histomorphometry; ChIP, mutagenesis, reporter, invasion assays\",\n      \"pmids\": [\"21590684\", \"21392388\", \"21176152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis for activation vs repression at different promoters not unified\", \"Survivin and MT1-MMP activation from single laboratories\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed ZBTB7A enforces survival and apoptosis resistance by directly repressing the pro-apoptotic Bim gene and by acting in a homeostatic NF-κB feedback loop activating p65 and IκBα promoters.\",\n      \"evidence\": \"ChIP, reporter assays, knockdown, flow cytometry, caspase-3 assays\",\n      \"pmids\": [\"22754333\", \"23054188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-laboratory studies\", \"Whether p65/IκBα activation is direct in physiological settings unconfirmed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Uncovered DNA-methylation-based silencing by ZBTB7A through direct MBD3 interaction recruiting the Mi-2/NuRD-HDAC complex and BCoR-linked DNMTs/HP1 to CDKN1A, and revealed context-dependent tumor suppression via SOX9 antagonism.\",\n      \"evidence\": \"Co-IP, ChIP, methylated/non-methylated EMSA, reporter; conditional prostate Zbtb7a KO with target gene analysis\",\n      \"pmids\": [\"23658227\", \"23727861\", \"23300578\", \"23355454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of DNMT-mediated methylation at the locus inferred from interactions\", \"Reconciliation of oncogenic ARF-repression with tumor-suppressive senescence bypass left to context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined ZBTB7A as a direct transcriptional repressor of glycolysis (GLUT3, PFKP, PKM) whose loss elevates glycolytic flux, and revealed a non-transcriptional role regulating BCL-X splicing via SAM68.\",\n      \"evidence\": \"ChIP, reporter, metabolic assays, KO/KD cell and mouse models, TCGA analysis; co-IP, RIP, splicing assays, HDAC inhibitor\",\n      \"pmids\": [\"25184678\", \"24514149\", \"25514493\", \"24857950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Smad4 and ETS-1 interactions are single-laboratory (ETS-1 low confidence)\", \"Mechanistic link between HDAC activity and splicing control incompletely defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Tied loss of ZBTB7A DNA binding to malignancy, showing cancer-derived zinc-finger mutations abolish binding, de-repress glycolytic targets, and enhance proliferation, and that ZBTB7A represses MCAM to restrain metastasis.\",\n      \"evidence\": \"Zinc-finger mutagenesis, reporter and metabolic assays, genome database mining; ChIP, reporter, invasion assays, melanoma specimens\",\n      \"pmids\": [\"26455326\", \"25995384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural consequences of mutations not yet resolved at this stage\", \"MCAM repression from single laboratory\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established ZBTB7A as a recurrently mutated gene in t(8;21) AML, with C-terminal zinc-finger mutations disrupting repressor and anti-proliferative activity, implying leukemogenic cooperation with RUNX1/RUNX1T1.\",\n      \"evidence\": \"Patient sequencing (23% of t(8;21) AML), reporter and proliferation assays of mutants\",\n      \"pmids\": [\"27252013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct functional cooperation with RUNX1-RUNX1T1 not yet demonstrated experimentally at this point\", \"Key downstream effector of the leukemic phenotype not pinpointed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified upstream regulation in erythroid cells (KLF1-driven expression of a novel transcript) and additional lineage-specific repressive targets, broadening the regulatory circuitry around ZBTB7A.\",\n      \"evidence\": \"ChIP, transcript analysis in erythroid differentiation; ChIP/reporter/RNA-IP in osteosarcoma (LINC00473)\",\n      \"pmids\": [\"29296711\", \"28942243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the erythroid-specific transcript not fully defined\", \"Single-laboratory target studies\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established ZBTB7A as a major direct repressor of fetal γ-globin via the -200 bp promoter element and, genome-wide, as a chromatin accessibility transducer required for NF-κB-driven inducible accessibility changes.\",\n      \"evidence\": \"CRISPR HPFH mutations, ChIP, EMSA, erythroid reporters; genome-wide ChIP-seq/ATAC-seq/RNA-seq with knockdown and p65 induction\",\n      \"pmids\": [\"29610478\", \"29813070\", \"29764865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ZBTB7A marks promoters for client-TF accessibility not molecularly resolved\", \"HP1γ–ZBTB7A axis from single laboratory\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined ZBTB7A's role in nuclear-receptor and metabolic circuits, showing AR-directed recruitment to E2F-Rb sites to suppress replication genes, reciprocal regulation with ERα/TRIM25, and hypoxic NF-κB repression de-repressing the MCT4 lactate exporter.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, co-IP, xenografts; reporter, ubiquitination, ChIP, oligonucleotide pulldown assays\",\n      \"pmids\": [\"31444154\", \"30265334\", \"31715186\", \"31271899\", \"30753838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Most signaling-loop studies from single laboratories\", \"Integration of these loops into a unified regulatory logic incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated ZBTB7A's role in cell-fate chromatin remodeling during pluripotency transitions and functionally confirmed t(8;21) leukemic cooperativity, with WT ZBTB7A blocking RUNX1-RUNX1T1-driven clonal expansion through glycolysis-coupled cell-cycle arrest.\",\n      \"evidence\": \"ATAC-seq/ChIP-seq/RNA-seq in BMP4-driven PNT; lentiviral WT/mutant expression in CD34+ cells, Seahorse, cell cycle, 2-DG\",\n      \"pmids\": [\"32393886\", \"32115572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dual opening/silencing activity during PNT mechanistically unexplained\", \"Molecular link between glycolysis repression and cell-cycle arrest in leukemia not fully traced\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the atomic basis of γ-globin repression, showing ZF1/ZF2 read the 5' C:G quadruplet and ZF4 the 3' quadruplet, and that the most disruptive HPFH mutations hit ZF1/ZF2-recognized bases.\",\n      \"evidence\": \"X-ray crystallography of the four-zinc-finger DBD bound to the -200 bp element plus mutant binding assays\",\n      \"pmids\": [\"34592153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full-length protein or POZ-mediated complexes on DNA not solved\", \"Does not address corepressor recruitment geometry\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended ZBTB7A's tumor-suppressive and metabolic repertoire to glioblastoma, showing direct repression of EPB41L5 (restraining EMT) and of HK2/LDHA (limiting glycolysis), with non-coding RNAs destabilizing ZBTB7A to release these programs.\",\n      \"evidence\": \"ChIP, RNA-seq, 3'UTR reporter, Seahorse, knockdown, in vivo tumor assays\",\n      \"pmids\": [\"36596853\", \"37066523\", \"36243002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GBM target studies from single laboratories\", \"Connection between oxidative-stress control in viral persistence and canonical transcription functions unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZBTB7A integrates its opposing activator/repressor and oncogenic/tumor-suppressive outputs—and what determines whether it opens or silences chromatin at a given locus as an accessibility transducer—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for context-dependent activation vs repression\", \"Molecular determinants of promoter selection for TF-induced accessibility unknown\", \"Structure of POZ-corepressor complexes on chromatin not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 9, 12, 24, 34, 36]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 4, 34, 43]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 10, 14, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7, 20]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 9, 12, 24, 34, 36]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9, 11, 12, 37, 42]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [24, 29, 46, 42]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [20, 36, 41]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 26, 37, 38]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 30, 42]}\n    ],\n    \"complexes\": [\n      \"Sin3A-HDAC corepressor complex\",\n      \"NCoR/SMRT corepressor complex\",\n      \"Mi-2/NuRD-HDAC complex (via MBD3)\",\n      \"ZBTB7A POZ-domain homodimer\"\n    ],\n    \"partners\": [\n      \"SP1\",\n      \"RELA\",\n      \"AR\",\n      \"SMAD4\",\n      \"KHDRBS1\",\n      \"SOX9\",\n      \"MBD3\",\n      \"SREBF1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}