{"gene":"ZBTB7B","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1996,"finding":"c-Krox (ZBTB7B) binds to multiple GC-rich sites in the promoters of both mouse alpha1(I) and alpha2(I) collagen genes. Structure/function analysis localized the transactivation domain to the zinc finger and C-terminal domains, and the dimerization domain to the C-terminal end of the protein.","method":"Electrophoretic mobility shift assays (EMSA), transient transfection/reporter assays, structure-function mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assays with mutagenesis defining functional domains, replicated across multiple promoter elements in same study","pmids":["8702912"],"is_preprint":false},{"year":1997,"finding":"c-Krox (ZBTB7B) binds to a site at approximately -248 to -230 in the human biglycan promoter, as confirmed using recombinant human c-Krox expressed in COS cells, implicating it in transcriptional regulation of biglycan in bone cells.","method":"DNase footprinting, EMSA, recombinant protein binding assay","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding confirmed with recombinant protein, single lab, single study","pmids":["9421237"],"is_preprint":false},{"year":2001,"finding":"hcKrox (ZBTB7B) represses the promoters of fibronectin, alpha1(I) collagen, alpha2(I) collagen, and elastin genes. The POZ domain and zinc-finger region mediate homo- and heterodimerization with related family members hcKrox-beta and hcKrox-gamma, as shown by co-immunoprecipitation and EMSA.","method":"Transient transfection reporter assays, EMSA, co-immunoprecipitation","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and functional reporter assays, single lab with two orthogonal methods","pmids":["11691585"],"is_preprint":false},{"year":2005,"finding":"c-Krox (ZBTB7B) overexpression inhibits radiosulfate incorporation into glycosaminoglycans and represses UDP-glucose dehydrogenase (UDPGD) gene transcription in articular chondrocytes through a cis-element between +18 and +39 bp of the UDPGD gene, likely acting in concert with Sp1/Sp3.","method":"Transient transfection reporter assays, decoy oligonucleotide experiments, radiosulfate incorporation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assays with decoy confirmation, single lab, two orthogonal methods","pmids":["15982635"],"is_preprint":false},{"year":2007,"finding":"Zbtb7b (ThPOK) promotes CD4 expression by antagonizing Runx3- and Runx1-mediated transcriptional repression of CD4. This antagonism is transcriptional, requires domains of Zbtb7b essential for CD4 lineage commitment in vivo, and is abolished by histone deacetylase inhibitor treatment, suggesting Zbtb7b acts by reducing expression of factors cooperating with Runx to repress CD4.","method":"In vitro reporter assays, in vivo genetic studies in mice, HDAC inhibitor treatment, domain-function analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo genetic epistasis with domain-function analysis, replicated across Runx1 and Runx3, multiple orthogonal approaches","pmids":["17878336"],"is_preprint":false},{"year":2011,"finding":"c-Krox (ZBTB7B) binds the proximal COL1A1 promoter and physically interacts with Sp1, Sp3, and the p65 subunit of NF-κB. NF-κB p65 is recruited to the promoter via protein-protein interaction with these trans-activators (including c-Krox) to inhibit COL1A1 transcription; siRNA knockdown of c-Krox prevented the p65 inhibitory effect on COL1A1 in scleroderma fibroblasts.","method":"ChIP, re-ChIP, co-immunoprecipitation, siRNA knockdown, reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP validated by re-ChIP, functional knockdown confirming mechanism, multiple orthogonal methods in one study","pmids":["22139845"],"is_preprint":false},{"year":2012,"finding":"A missense mutation in the BTB-POZ domain of ZBTB7B (helpless mouse) intrinsically disrupts NKT cell subset development: mutant mice have NKT cells that lack CD4, gain CD8, are hyperproliferative, express RORγt, and predominantly produce IL-17 instead of IFN-γ, demonstrating ZBTB7B genetically controls the balance of NKT effector subsets.","method":"Genetic mouse model with BTB-POZ domain missense mutation, flow cytometry, cytokine profiling","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic loss-of-function model with domain-specific mutation and multiple defined cellular phenotype readouts","pmids":["23105140"],"is_preprint":false},{"year":2017,"finding":"Zbtb7b is required for activation of the thermogenic gene program in brown and beige adipocytes. Mechanistically, Zbtb7b recruits the Blnc1/hnRNPU ribonucleoprotein complex (identified by proteomic analysis) to activate thermogenic gene expression. Genetic ablation of Zbtb7b impairs cold-induced transcriptional remodeling in brown fat and reduces beige fat browning.","method":"Genome-wide functional screen, genetic ablation (knockout mice), proteomic analysis, cold-challenge phenotyping","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined thermogenic phenotype plus proteomic identification of complex, multiple orthogonal methods","pmids":["28784777"],"is_preprint":false},{"year":2020,"finding":"Zbtb7b suppresses irradiation-induced IL-6 production by recruiting the RNA demethylase ALKBH5 to IL6 mRNA, leading to demethylation of N6-methyladenosine (m6A) on IL6 mRNA and inhibition of its nuclear export.","method":"siRNA knockdown, RNA co-immunoprecipitation, m6A quantification, nuclear export assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNA-protein interaction and functional m6A/export assays, single lab, single study","pmids":["32828308"],"is_preprint":false},{"year":2020,"finding":"The R367Q mutation in the first DNA-binding zinc finger domain of ThPOK (ZBTB7B) impairs DNA binding by loss of base contact in the major groove, causing severe reduction of CD4 single-positive T cells and dampened proinflammatory immune responses in vivo. ChIP-seq identified transcriptional networks regulated by ThPOK-containing chromatin complexes relevant to T cell lineage specification.","method":"ENU mutagenesis screen, structural prediction, ChIP-seq, flow cytometry, ex vivo cytokine assays","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional domain mutation with structural prediction, ChIP-seq confirmation of chromatin occupancy, in vivo immune phenotyping","pmids":["31792077"],"is_preprint":false},{"year":2024,"finding":"ZBTB7B acts as a permissive regulator of HCC initiation by directly repressing c-Jun expression and competing with c-Jun for chromatin binding. ZBTB7B deficiency down-regulates adult liver-specific gene expression, primes livers to a fetal-like state, and accelerates HCC initiation; knockdown or dominant-negative c-Jun delayed HCC in ZBTB7B-deficient livers.","method":"Hepatocyte-specific knockout mouse model, transcriptomic analysis, phosphoproteomic analysis, ChIP-seq, luciferase reporter, rescue experiments with c-Jun knockdown","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — integrated multi-omics (transcriptomic, phosphoproteomic, ChIP-seq) with genetic rescue, multiple orthogonal methods","pmids":["38225233"],"is_preprint":false},{"year":2024,"finding":"ZBTB7B transcriptionally activates the LDHA promoter to regulate glycolysis; its transcriptional activity is stabilized by SUMOylation. ALDH1A1 acts upstream of ZBTB7B in this pathway; binding sites of ZBTB7B on the LDHA promoter were mapped by luciferase reporter and ChIP-qPCR.","method":"Luciferase reporter assay, ChIP-qPCR, RNA-seq, western blot, SUMOylation assay, xenograft mouse models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by ChIP-qPCR and reporter assay, SUMOylation assessed, single lab","pmids":["39107297"],"is_preprint":false},{"year":2024,"finding":"Zbtb7b suppresses expression of the lncRNA H19 to attenuate hepatic de novo lipogenesis and increase fatty acid oxidation in MASLD-related HCC, protecting against lipid accumulation in hepatocytes.","method":"Liver-specific Zbtb7b knockout mouse model, gene expression analysis, lipid metabolism assays","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic KO with defined metabolic phenotype but limited mechanistic follow-up on H19 suppression mechanism, single lab","pmids":["39714087"],"is_preprint":false},{"year":2025,"finding":"ZBTB7B co-localizes and directly binds to the androgen receptor (AR) via the N-terminal domain (NTD) of AR. ZBTB7B depletion reduces AR expression, suppresses AR nuclear translocation and stability, and promotes AR ubiquitination and proteasomal degradation in LNCaP prostate cancer cells, acting upstream of AR.","method":"Co-immunoprecipitation, immunofluorescence co-localization, cycloheximide chase, ubiquitination assay, domain-mapping in HEK293 cells, siRNA knockdown","journal":"Translational cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mapping and multiple mechanistic assays, single lab","pmids":["41378003"],"is_preprint":false},{"year":2025,"finding":"ZBTB7B represses breast cancer EMT by suppressing expression of EMT genes, WNT/β-catenin target genes, and pro-metastatic TGFβ pathway components, restricting breast cancer cells to a luminal epithelial phenotype. This repressive function is associated with super-enhancer regulation of ZBTB7B itself.","method":"Super-enhancer profiling, master regulator activity inference, ThPOK overexpression/knockdown in breast cancer cell lines, gene expression analysis","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional manipulation in cell lines with transcriptomic readout and SE profiling, single lab, multiple methods","pmids":["41231242"],"is_preprint":false},{"year":2026,"finding":"ZBTB7B transcriptionally activates GPR17 expression in glioma cells, suppressing PKA phosphorylation, amplifying mitochondrial ROS, and triggering Caspase3-dependent apoptosis; ZBTB7B also upregulates CXCL10 secretion to enhance CD4+ and CD8+ T cell tumor infiltration.","method":"Lentiviral overexpression, in vitro and xenograft assays, gene expression analysis, multiplex immunofluorescence on tissue microarray","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional overexpression with defined pathway readouts but mechanistic detail on direct transcriptional activation of GPR17 not fully elaborated in abstract, single lab","pmids":["41294275"],"is_preprint":false},{"year":2026,"finding":"ZBTB7B transcriptionally activates ADPGK (a non-canonical glycolytic enzyme) expression. The E3 ubiquitin ligase NEDD4 directly interacts with ZBTB7B, mediates its ubiquitination at K450, and targets it for proteasomal degradation, thereby suppressing ADPGK expression and glycolysis in lung adenocarcinoma.","method":"Reporter assay, ChIP, co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis (K450), in vitro and in vivo tumor models","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct NEDD4-ZBTB7B interaction with ubiquitination site identified by mutagenesis and functional rescue, single lab, multiple orthogonal methods","pmids":["41807371"],"is_preprint":false}],"current_model":"ZBTB7B (ThPOK/c-Krox) is a BTB-POZ and zinc finger transcription factor that binds GC-rich DNA elements through its zinc finger domain to activate or repress target genes (including type I collagens, LDHA, ADPGK, GPR17, c-Jun, H19); it promotes CD4 T cell lineage commitment and thermogenic adipocyte gene programs by antagonizing Runx-mediated repression and recruiting lncRNA/hnRNP complexes, respectively; its activity is regulated post-translationally by NEDD4-mediated ubiquitination (K450) and SUMOylation; and it physically interacts with partners including Sp1/Sp3/NF-κB p65, ALKBH5, Blnc1/hnRNPU, and the androgen receptor NTD to modulate transcription, m6A RNA methylation, and protein stability in a context-dependent manner."},"narrative":{"mechanistic_narrative":"ZBTB7B (ThPOK/c-Krox) is a BTB-POZ and zinc finger transcription factor that binds GC-rich promoter elements to either activate or repress target genes, governing extracellular matrix production, T cell lineage commitment, and adipocyte and tumor metabolic programs [PMID:8702912, PMID:17878336]. Its zinc finger and C-terminal domains carry transactivation activity while the POZ domain mediates homo- and heterodimerization with related family members [PMID:8702912, PMID:11691585], and DNA recognition depends on base contacts made by the first zinc finger, since the R367Q mutation abolishes major-groove binding and collapses CD4 T cell development [PMID:31792077]. In matrix-producing cells it directly occupies the COL1A1 and other collagen, fibronectin, and elastin promoters, cooperating with Sp1/Sp3 and acting as a docking platform that recruits NF-κB p65 to repress collagen transcription [PMID:11691585, PMID:15982635, PMID:22139845]. In the immune system it promotes CD4 expression by antagonizing Runx1/Runx3-mediated repression and controls the effector balance of NKT cells, with BTB-POZ domain mutation skewing them toward an IL-17-producing RORγt+ phenotype [PMID:17878336, PMID:23105140]. ZBTB7B also acts beyond classical transcription: it recruits the Blnc1/hnRNPU ribonucleoprotein complex to drive the brown/beige adipocyte thermogenic program [PMID:28784777] and recruits the m6A demethylase ALKBH5 to IL6 mRNA to limit its nuclear export [PMID:32828308]. In cancer contexts it directly represses c-Jun to maintain adult hepatocyte identity and restrain HCC initiation [PMID:38225233], activates the glycolytic genes LDHA and ADPGK [PMID:39107297, PMID:41807371], suppresses the lncRNA H19 to limit hepatic lipogenesis [PMID:39714087], and restricts breast cancer EMT by repressing WNT and TGFβ programs [PMID:41231242]. Its protein level and activity are tuned post-translationally by SUMOylation, which stabilizes its transcriptional activity [PMID:39107297], and by NEDD4-mediated ubiquitination at K450, which targets it for proteasomal degradation [PMID:41807371].","teleology":[{"year":1996,"claim":"Established ZBTB7B as a sequence-specific DNA-binding transcription factor for GC-rich elements and localized its functional domains, defining the molecular basis of its transcriptional activity.","evidence":"EMSA, reporter assays, and structure-function mutagenesis on collagen alpha1(I)/alpha2(I) promoters","pmids":["8702912"],"confidence":"High","gaps":["Did not establish whether the factor activates or represses in physiological context","No genome-wide binding map","Endogenous target repertoire unknown"]},{"year":2001,"claim":"Showed ZBTB7B functions as a repressor of multiple ECM genes and dimerizes through its POZ and zinc-finger regions, framing it as a multimeric transcriptional regulator of matrix gene expression.","evidence":"Reporter assays, EMSA, and co-immunoprecipitation of hcKrox isoforms","pmids":["11691585"],"confidence":"Medium","gaps":["Dimer composition in vivo not defined","Single lab","Cofactors mediating repression not identified at this stage"]},{"year":2011,"claim":"Resolved how ZBTB7B represses COL1A1 by binding the proximal promoter and recruiting NF-κB p65 via Sp1/Sp3, establishing a protein-interaction-based mechanism for matrix gene repression.","evidence":"ChIP, re-ChIP, co-IP, siRNA knockdown, and reporter assays in scleroderma fibroblasts","pmids":["22139845"],"confidence":"High","gaps":["Structural basis of the multiprotein complex unresolved","Generality beyond collagen promoters not tested"]},{"year":2007,"claim":"Defined the developmental logic by which ZBTB7B drives CD4 T cell commitment, showing it antagonizes Runx-mediated CD4 repression through an HDAC-sensitive transcriptional mechanism.","evidence":"In vitro reporter assays, in vivo mouse genetics, HDAC inhibitor treatment, and domain-function analysis across Runx1/Runx3","pmids":["17878336"],"confidence":"High","gaps":["Direct targets cooperating with Runx not fully enumerated","Precise chromatin mechanism of antagonism unresolved"]},{"year":2012,"claim":"Demonstrated that the BTB-POZ domain is required for ZBTB7B control of NKT effector subset balance, linking a specific domain to in vivo lineage and cytokine outcomes.","evidence":"BTB-POZ domain missense mutant mouse, flow cytometry, and cytokine profiling","pmids":["23105140"],"confidence":"High","gaps":["Molecular partners engaged by the BTB-POZ domain in NKT cells not identified","Target genes driving the IL-17 vs IFN-γ switch not mapped"]},{"year":2017,"claim":"Extended ZBTB7B function beyond classical transcription by showing it recruits a Blnc1/hnRNPU ribonucleoprotein complex to activate the thermogenic gene program in brown/beige fat.","evidence":"Genome-wide screen, knockout mice, proteomic identification of partners, and cold-challenge phenotyping","pmids":["28784777"],"confidence":"High","gaps":["How the lncRNP complex is targeted to thermogenic loci is unresolved","Direct DNA-binding contribution vs RNP scaffolding not separated"]},{"year":2020,"claim":"Revealed a post-transcriptional role in which ZBTB7B recruits ALKBH5 to demethylate IL6 mRNA and block its nuclear export, implicating it in m6A-dependent RNA regulation.","evidence":"siRNA knockdown, RNA co-IP, m6A quantification, and nuclear export assays","pmids":["32828308"],"confidence":"Medium","gaps":["Single lab, single study","Direct vs indirect ZBTB7B-ALKBH5-mRNA recruitment not structurally defined","Breadth of mRNA targets unknown"]},{"year":2020,"claim":"Pinpointed the first zinc finger as the determinant of DNA recognition and provided a genome-wide map of ThPOK chromatin occupancy in T cell lineage specification.","evidence":"ENU mutagenesis (R367Q), structural prediction, ChIP-seq, and in vivo immune phenotyping","pmids":["31792077"],"confidence":"High","gaps":["Full target network not functionally validated","Cofactor composition at occupied sites not resolved"]},{"year":2024,"claim":"Established ZBTB7B as a guardian of adult hepatocyte identity that directly represses and competes with c-Jun, restraining HCC initiation.","evidence":"Hepatocyte-specific knockout, multi-omics (transcriptomic, phosphoproteomic, ChIP-seq), reporter assays, and c-Jun knockdown rescue","pmids":["38225233"],"confidence":"High","gaps":["Mechanism of chromatin competition with c-Jun not structurally defined","Upstream signals controlling ZBTB7B in liver unclear"]},{"year":2024,"claim":"Linked ZBTB7B to glycolytic and lipid metabolic control in cancer, showing it activates LDHA (stabilized by SUMOylation) and suppresses lncRNA H19 to limit hepatic lipogenesis.","evidence":"Luciferase reporter, ChIP-qPCR, RNA-seq, SUMOylation assay, and liver-specific knockout metabolic phenotyping","pmids":["39107297","39714087"],"confidence":"Medium","gaps":["SUMOylation site and machinery not mapped","Mechanism of H19 suppression not detailed","Single lab per study"]},{"year":2025,"claim":"Showed ZBTB7B physically engages the androgen receptor NTD and restricts AR-driven and EMT programs, broadening its repressive role to additional cancer contexts.","evidence":"Co-IP, immunofluorescence, cycloheximide chase, ubiquitination assays, domain mapping; and super-enhancer profiling with ThPOK manipulation in breast cancer lines","pmids":["41378003","41231242"],"confidence":"Medium","gaps":["Whether AR effects are transcriptional vs stability-based not fully separated","Direct DNA targets in EMT repression not mapped","Single lab per study"]},{"year":2026,"claim":"Defined post-translational control of ZBTB7B stability by NEDD4-mediated K450 ubiquitination and linked ZBTB7B to activation of metabolic (ADPGK, GPR17) and immune-infiltration (CXCL10) programs in tumors.","evidence":"Reporter assays, ChIP, co-IP, site-specific ubiquitination mutagenesis (K450), lentiviral overexpression, and in vitro/xenograft tumor models","pmids":["41807371","41294275"],"confidence":"Medium","gaps":["Directness of GPR17/CXCL10 transcriptional activation not fully elaborated","Signals regulating NEDD4-ZBTB7B in vivo unclear","Single lab per study"]},{"year":null,"claim":"How ZBTB7B switches between activator, repressor, and RNA/m6A-regulatory modes across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking cofactor selection to activation vs repression","Structural basis of partner choice (Sp1/Sp3, p65, hnRNPU, ALKBH5, AR) unknown","Integration of SUMO and NEDD4 post-translational control with context-specific outputs undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,4,5,10,11,16]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,9,10]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,5,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6,9]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,11,12,16]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,14,15]}],"complexes":["Blnc1/hnRNPU ribonucleoprotein complex"],"partners":["SP1","SP3","RELA","HNRNPU","ALKBH5","AR","NEDD4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15156","full_name":"Zinc finger and BTB domain-containing protein 7B","aliases":["Krueppel-related zinc finger protein cKrox","hcKrox","T-helper-inducing POZ/Krueppel-like factor","Zinc finger and BTB domain-containing protein 15","Zinc finger protein 67 homolog","Zfp-67","Zinc finger protein 857B","Zinc finger protein Th-POK"],"length_aa":539,"mass_kda":58.0,"function":"Transcription regulator that acts as a key regulator of lineage commitment of immature T-cell precursors. Exerts distinct biological functions in the mammary epithelial cells and T cells in a tissue-specific manner. Necessary and sufficient for commitment of CD4 lineage, while its absence causes CD8 commitment. Development of immature T-cell precursors (thymocytes) to either the CD4 helper or CD8 killer T-cell lineages correlates precisely with their T-cell receptor specificity for major histocompatibility complex class II or class I molecules, respectively. Cross-antagonism between ZBTB7B and CBF complexes are determinative to CD4 versus CD8 cell fate decision. Suppresses RUNX3 expression and imposes CD4+ lineage fate by inducing the SOCS suppressors of cytokine signaling. induces, as a transcriptional activator, SOCS genes expression which represses RUNX3 expression and promotes the CD4+ lineage fate. During CD4 lineage commitment, associates with multiple sites at the CD8 locus, acting as a negative regulator of the CD8 promoter and enhancers by epigenetic silencing through the recruitment of class II histone deacetylases, such as HDAC4 and HDAC5, to these loci. Regulates the development of IL17-producing CD1d-restricted naural killer (NK) T cells. Also functions as an important metabolic regulator in the lactating mammary glands. Critical feed-forward regulator of insulin signaling in mammary gland lactation, directly regulates expression of insulin receptor substrate-1 (IRS-1) and insulin-induced Akt-mTOR-SREBP signaling (By similarity). Transcriptional repressor of the collagen COL1A1 and COL1A2 genes. May also function as a repressor of fibronectin and possibly other extracellular matrix genes (PubMed:9370309). Potent driver of brown fat development, thermogenesis and cold-induced beige fat formation. Recruits the brown fat lncRNA 1 (Blnc1):HNRNPU ribonucleoprotein complex to activate thermogenic gene expression in brown and beige adipocytes (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O15156/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZBTB7B","classification":"Not Classified","n_dependent_lines":61,"n_total_lines":1208,"dependency_fraction":0.050496688741721855},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZBTB7B","total_profiled":1310},"omim":[{"mim_id":"611735","title":"CUB DOMAIN-CONTAINING PROTEIN 1; CDCP1","url":"https://www.omim.org/entry/611735"},{"mim_id":"607646","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 7B; ZBTB7B","url":"https://www.omim.org/entry/607646"},{"mim_id":"176797","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 16; ZBTB16","url":"https://www.omim.org/entry/176797"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZBTB7B"},"hgnc":{"alias_symbol":["ZBTB15","c-Krox","hcKrox","ZNF857B","vGAF","ThPOK"],"prev_symbol":["ZFP67"]},"alphafold":{"accession":"O15156","domains":[{"cath_id":"-","chopping":"43-65_96-149","consensus_level":"medium","plddt":45.4535,"start":43,"end":149}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15156","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15156-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15156-F1-predicted_aligned_error_v6.png","plddt_mean":55.09},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZBTB7B","jax_strain_url":"https://www.jax.org/strain/search?query=ZBTB7B"},"sequence":{"accession":"O15156","fasta_url":"https://rest.uniprot.org/uniprotkb/O15156.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15156/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15156"}},"corpus_meta":[{"pmid":"28784777","id":"PMC_28784777","title":"Zbtb7b engages the long noncoding RNA Blnc1 to drive brown and beige fat development and thermogenesis.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28784777","citation_count":77,"is_preprint":false},{"pmid":"17878336","id":"PMC_17878336","title":"The transcription factor Zbtb7b promotes CD4 expression by antagonizing Runx-mediated activation of the CD4 silencer.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17878336","citation_count":76,"is_preprint":false},{"pmid":"8702912","id":"PMC_8702912","title":"c-Krox binds to several sites in the promoter of both mouse type I collagen genes. Structure/function study and developmental expression analysis.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8702912","citation_count":58,"is_preprint":false},{"pmid":"22139845","id":"PMC_22139845","title":"The p65 subunit of NF-κB inhibits COL1A1 gene transcription in human dermal and scleroderma fibroblasts through its recruitment on promoter by protein interaction with transcriptional activators (c-Krox, Sp1, and Sp3).","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22139845","citation_count":56,"is_preprint":false},{"pmid":"23105140","id":"PMC_23105140","title":"ZBTB7B (Th-POK) regulates the development of IL-17-producing CD1d-restricted mouse NKT cells.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23105140","citation_count":39,"is_preprint":false},{"pmid":"11691585","id":"PMC_11691585","title":"The hcKrox gene family regulates multiple extracellular matrix genes.","date":"2001","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/11691585","citation_count":35,"is_preprint":false},{"pmid":"9421237","id":"PMC_9421237","title":"Functional characterization of the human biglycan 5'-flanking DNA and binding of the transcription factor c-Krox.","date":"1997","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/9421237","citation_count":25,"is_preprint":false},{"pmid":"35941174","id":"PMC_35941174","title":"A novel high-risk subpopulation identified by CTSL and ZBTB7B in gastric cancer.","date":"2022","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35941174","citation_count":23,"is_preprint":false},{"pmid":"32828308","id":"PMC_32828308","title":"Zbtb7b suppresses aseptic inflammation by regulating m6A modification of IL6 mRNA.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32828308","citation_count":22,"is_preprint":false},{"pmid":"39107297","id":"PMC_39107297","title":"ALDH1A1 promotes immune escape of tumor cells through ZBTB7B-glycolysis pathway.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39107297","citation_count":17,"is_preprint":false},{"pmid":"15982635","id":"PMC_15982635","title":"c-Krox down-regulates the expression of UDP-glucose dehydrogenase in chondrocytes.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15982635","citation_count":16,"is_preprint":false},{"pmid":"35761286","id":"PMC_35761286","title":"Epigenetic DNA methylation of Zbtb7b regulates the population of double-positive CD4+CD8+ T cells in ulcerative colitis.","date":"2022","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35761286","citation_count":13,"is_preprint":false},{"pmid":"31792077","id":"PMC_31792077","title":"ZBTB7B (ThPOK) Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis.","date":"2020","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/31792077","citation_count":8,"is_preprint":false},{"pmid":"18298657","id":"PMC_18298657","title":"Chondroitin sulphate decreases collagen synthesis in normal and scleroderma fibroblasts through a Smad-independent TGF-beta pathway--implication of C-Krox and Sp1.","date":"2008","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18298657","citation_count":8,"is_preprint":false},{"pmid":"38225233","id":"PMC_38225233","title":"ZBTB7B is a permissive regulator of hepatocellular carcinoma initiation by repressing c-Jun expression and function.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38225233","citation_count":6,"is_preprint":false},{"pmid":"33994355","id":"PMC_33994355","title":"Role of vertebrate GAGA associated factor (vGAF) in early development of zebrafish.","date":"2021","source":"Cells & development","url":"https://pubmed.ncbi.nlm.nih.gov/33994355","citation_count":4,"is_preprint":false},{"pmid":"39714087","id":"PMC_39714087","title":"Zbtb7b defines a compensatory mechanism in MASLD-related HCC progression by suppressing H19-mediated hepatic lipid deposition.","date":"2024","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/39714087","citation_count":1,"is_preprint":false},{"pmid":"33627571","id":"PMC_33627571","title":"Zbtb7a and Zbtb7b: Opening naïve loci to reprogram ESCs.","date":"2021","source":"Bioscience trends","url":"https://pubmed.ncbi.nlm.nih.gov/33627571","citation_count":1,"is_preprint":false},{"pmid":"41294275","id":"PMC_41294275","title":"ZBTB7B inhibits glioma tumorigenicity by upregulating GPR17 and CXCL10.","date":"2026","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/41294275","citation_count":0,"is_preprint":false},{"pmid":"41378003","id":"PMC_41378003","title":"ZBTB7B modulates the androgen receptor as an upstream regulator via colocalization and direct binding in LNCaP prostate cancer cells.","date":"2025","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41378003","citation_count":0,"is_preprint":false},{"pmid":"41807371","id":"PMC_41807371","title":"Inhibition of ZBTB7B-mediated ADPGK transcription by NEDD4 impedes glycolysis and progression of lung adenocarcinoma.","date":"2026","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/41807371","citation_count":0,"is_preprint":false},{"pmid":"39386673","id":"PMC_39386673","title":"Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4 + cell lineage commitment factor, as a master regulator that restricts breast cancer cells to a luminal non-migratory phenotype.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39386673","citation_count":0,"is_preprint":false},{"pmid":"41231242","id":"PMC_41231242","title":"Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4+ cell lineage commitment factor, as a master regulator that restricts breast cancer cells to a luminal non-migratory phenotype.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/41231242","citation_count":0,"is_preprint":false},{"pmid":"40235471","id":"PMC_40235471","title":"Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4+ cell lineage commitment factor, as a master regulator that restricts breast cancer cells to a luminal non-migratory phenotype.","date":"2025","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/40235471","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.21.614267","title":"Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4  <sup>+</sup>  cell lineage commitment factor, as a master regulator that restricts breast cancer cells to a luminal non-migratory phenotype","date":"2024-09-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.21.614267","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14938,"output_tokens":4234,"usd":0.054162,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12166,"output_tokens":4317,"usd":0.084377,"stage2_stop_reason":"end_turn"},"total_usd":0.138539,"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\": 1996,\n      \"finding\": \"c-Krox (ZBTB7B) binds to multiple GC-rich sites in the promoters of both mouse alpha1(I) and alpha2(I) collagen genes. Structure/function analysis localized the transactivation domain to the zinc finger and C-terminal domains, and the dimerization domain to the C-terminal end of the protein.\",\n      \"method\": \"Electrophoretic mobility shift assays (EMSA), transient transfection/reporter assays, structure-function mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assays with mutagenesis defining functional domains, replicated across multiple promoter elements in same study\",\n      \"pmids\": [\"8702912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"c-Krox (ZBTB7B) binds to a site at approximately -248 to -230 in the human biglycan promoter, as confirmed using recombinant human c-Krox expressed in COS cells, implicating it in transcriptional regulation of biglycan in bone cells.\",\n      \"method\": \"DNase footprinting, EMSA, recombinant protein binding assay\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding confirmed with recombinant protein, single lab, single study\",\n      \"pmids\": [\"9421237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"hcKrox (ZBTB7B) represses the promoters of fibronectin, alpha1(I) collagen, alpha2(I) collagen, and elastin genes. The POZ domain and zinc-finger region mediate homo- and heterodimerization with related family members hcKrox-beta and hcKrox-gamma, as shown by co-immunoprecipitation and EMSA.\",\n      \"method\": \"Transient transfection reporter assays, EMSA, co-immunoprecipitation\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and functional reporter assays, single lab with two orthogonal methods\",\n      \"pmids\": [\"11691585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Krox (ZBTB7B) overexpression inhibits radiosulfate incorporation into glycosaminoglycans and represses UDP-glucose dehydrogenase (UDPGD) gene transcription in articular chondrocytes through a cis-element between +18 and +39 bp of the UDPGD gene, likely acting in concert with Sp1/Sp3.\",\n      \"method\": \"Transient transfection reporter assays, decoy oligonucleotide experiments, radiosulfate incorporation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assays with decoy confirmation, single lab, two orthogonal methods\",\n      \"pmids\": [\"15982635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Zbtb7b (ThPOK) promotes CD4 expression by antagonizing Runx3- and Runx1-mediated transcriptional repression of CD4. This antagonism is transcriptional, requires domains of Zbtb7b essential for CD4 lineage commitment in vivo, and is abolished by histone deacetylase inhibitor treatment, suggesting Zbtb7b acts by reducing expression of factors cooperating with Runx to repress CD4.\",\n      \"method\": \"In vitro reporter assays, in vivo genetic studies in mice, HDAC inhibitor treatment, domain-function analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo genetic epistasis with domain-function analysis, replicated across Runx1 and Runx3, multiple orthogonal approaches\",\n      \"pmids\": [\"17878336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"c-Krox (ZBTB7B) binds the proximal COL1A1 promoter and physically interacts with Sp1, Sp3, and the p65 subunit of NF-κB. NF-κB p65 is recruited to the promoter via protein-protein interaction with these trans-activators (including c-Krox) to inhibit COL1A1 transcription; siRNA knockdown of c-Krox prevented the p65 inhibitory effect on COL1A1 in scleroderma fibroblasts.\",\n      \"method\": \"ChIP, re-ChIP, co-immunoprecipitation, siRNA knockdown, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP validated by re-ChIP, functional knockdown confirming mechanism, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22139845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A missense mutation in the BTB-POZ domain of ZBTB7B (helpless mouse) intrinsically disrupts NKT cell subset development: mutant mice have NKT cells that lack CD4, gain CD8, are hyperproliferative, express RORγt, and predominantly produce IL-17 instead of IFN-γ, demonstrating ZBTB7B genetically controls the balance of NKT effector subsets.\",\n      \"method\": \"Genetic mouse model with BTB-POZ domain missense mutation, flow cytometry, cytokine profiling\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic loss-of-function model with domain-specific mutation and multiple defined cellular phenotype readouts\",\n      \"pmids\": [\"23105140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Zbtb7b is required for activation of the thermogenic gene program in brown and beige adipocytes. Mechanistically, Zbtb7b recruits the Blnc1/hnRNPU ribonucleoprotein complex (identified by proteomic analysis) to activate thermogenic gene expression. Genetic ablation of Zbtb7b impairs cold-induced transcriptional remodeling in brown fat and reduces beige fat browning.\",\n      \"method\": \"Genome-wide functional screen, genetic ablation (knockout mice), proteomic analysis, cold-challenge phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined thermogenic phenotype plus proteomic identification of complex, multiple orthogonal methods\",\n      \"pmids\": [\"28784777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Zbtb7b suppresses irradiation-induced IL-6 production by recruiting the RNA demethylase ALKBH5 to IL6 mRNA, leading to demethylation of N6-methyladenosine (m6A) on IL6 mRNA and inhibition of its nuclear export.\",\n      \"method\": \"siRNA knockdown, RNA co-immunoprecipitation, m6A quantification, nuclear export assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNA-protein interaction and functional m6A/export assays, single lab, single study\",\n      \"pmids\": [\"32828308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The R367Q mutation in the first DNA-binding zinc finger domain of ThPOK (ZBTB7B) impairs DNA binding by loss of base contact in the major groove, causing severe reduction of CD4 single-positive T cells and dampened proinflammatory immune responses in vivo. ChIP-seq identified transcriptional networks regulated by ThPOK-containing chromatin complexes relevant to T cell lineage specification.\",\n      \"method\": \"ENU mutagenesis screen, structural prediction, ChIP-seq, flow cytometry, ex vivo cytokine assays\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional domain mutation with structural prediction, ChIP-seq confirmation of chromatin occupancy, in vivo immune phenotyping\",\n      \"pmids\": [\"31792077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZBTB7B acts as a permissive regulator of HCC initiation by directly repressing c-Jun expression and competing with c-Jun for chromatin binding. ZBTB7B deficiency down-regulates adult liver-specific gene expression, primes livers to a fetal-like state, and accelerates HCC initiation; knockdown or dominant-negative c-Jun delayed HCC in ZBTB7B-deficient livers.\",\n      \"method\": \"Hepatocyte-specific knockout mouse model, transcriptomic analysis, phosphoproteomic analysis, ChIP-seq, luciferase reporter, rescue experiments with c-Jun knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — integrated multi-omics (transcriptomic, phosphoproteomic, ChIP-seq) with genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"38225233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZBTB7B transcriptionally activates the LDHA promoter to regulate glycolysis; its transcriptional activity is stabilized by SUMOylation. ALDH1A1 acts upstream of ZBTB7B in this pathway; binding sites of ZBTB7B on the LDHA promoter were mapped by luciferase reporter and ChIP-qPCR.\",\n      \"method\": \"Luciferase reporter assay, ChIP-qPCR, RNA-seq, western blot, SUMOylation assay, xenograft mouse models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by ChIP-qPCR and reporter assay, SUMOylation assessed, single lab\",\n      \"pmids\": [\"39107297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Zbtb7b suppresses expression of the lncRNA H19 to attenuate hepatic de novo lipogenesis and increase fatty acid oxidation in MASLD-related HCC, protecting against lipid accumulation in hepatocytes.\",\n      \"method\": \"Liver-specific Zbtb7b knockout mouse model, gene expression analysis, lipid metabolism assays\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic KO with defined metabolic phenotype but limited mechanistic follow-up on H19 suppression mechanism, single lab\",\n      \"pmids\": [\"39714087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZBTB7B co-localizes and directly binds to the androgen receptor (AR) via the N-terminal domain (NTD) of AR. ZBTB7B depletion reduces AR expression, suppresses AR nuclear translocation and stability, and promotes AR ubiquitination and proteasomal degradation in LNCaP prostate cancer cells, acting upstream of AR.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, cycloheximide chase, ubiquitination assay, domain-mapping in HEK293 cells, siRNA knockdown\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mapping and multiple mechanistic assays, single lab\",\n      \"pmids\": [\"41378003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZBTB7B represses breast cancer EMT by suppressing expression of EMT genes, WNT/β-catenin target genes, and pro-metastatic TGFβ pathway components, restricting breast cancer cells to a luminal epithelial phenotype. This repressive function is associated with super-enhancer regulation of ZBTB7B itself.\",\n      \"method\": \"Super-enhancer profiling, master regulator activity inference, ThPOK overexpression/knockdown in breast cancer cell lines, gene expression analysis\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional manipulation in cell lines with transcriptomic readout and SE profiling, single lab, multiple methods\",\n      \"pmids\": [\"41231242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZBTB7B transcriptionally activates GPR17 expression in glioma cells, suppressing PKA phosphorylation, amplifying mitochondrial ROS, and triggering Caspase3-dependent apoptosis; ZBTB7B also upregulates CXCL10 secretion to enhance CD4+ and CD8+ T cell tumor infiltration.\",\n      \"method\": \"Lentiviral overexpression, in vitro and xenograft assays, gene expression analysis, multiplex immunofluorescence on tissue microarray\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional overexpression with defined pathway readouts but mechanistic detail on direct transcriptional activation of GPR17 not fully elaborated in abstract, single lab\",\n      \"pmids\": [\"41294275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZBTB7B transcriptionally activates ADPGK (a non-canonical glycolytic enzyme) expression. The E3 ubiquitin ligase NEDD4 directly interacts with ZBTB7B, mediates its ubiquitination at K450, and targets it for proteasomal degradation, thereby suppressing ADPGK expression and glycolysis in lung adenocarcinoma.\",\n      \"method\": \"Reporter assay, ChIP, co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis (K450), in vitro and in vivo tumor models\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct NEDD4-ZBTB7B interaction with ubiquitination site identified by mutagenesis and functional rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41807371\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZBTB7B (ThPOK/c-Krox) is a BTB-POZ and zinc finger transcription factor that binds GC-rich DNA elements through its zinc finger domain to activate or repress target genes (including type I collagens, LDHA, ADPGK, GPR17, c-Jun, H19); it promotes CD4 T cell lineage commitment and thermogenic adipocyte gene programs by antagonizing Runx-mediated repression and recruiting lncRNA/hnRNP complexes, respectively; its activity is regulated post-translationally by NEDD4-mediated ubiquitination (K450) and SUMOylation; and it physically interacts with partners including Sp1/Sp3/NF-κB p65, ALKBH5, Blnc1/hnRNPU, and the androgen receptor NTD to modulate transcription, m6A RNA methylation, and protein stability in a context-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZBTB7B (ThPOK/c-Krox) is a BTB-POZ and zinc finger transcription factor that binds GC-rich promoter elements to either activate or repress target genes, governing extracellular matrix production, T cell lineage commitment, and adipocyte and tumor metabolic programs [#0, #4]. Its zinc finger and C-terminal domains carry transactivation activity while the POZ domain mediates homo- and heterodimerization with related family members [#0, #2], and DNA recognition depends on base contacts made by the first zinc finger, since the R367Q mutation abolishes major-groove binding and collapses CD4 T cell development [#9]. In matrix-producing cells it directly occupies the COL1A1 and other collagen, fibronectin, and elastin promoters, cooperating with Sp1/Sp3 and acting as a docking platform that recruits NF-\\u03baB p65 to repress collagen transcription [#2, #3, #5]. In the immune system it promotes CD4 expression by antagonizing Runx1/Runx3-mediated repression and controls the effector balance of NKT cells, with BTB-POZ domain mutation skewing them toward an IL-17-producing ROR\\u03b3t+ phenotype [#4, #6]. ZBTB7B also acts beyond classical transcription: it recruits the Blnc1/hnRNPU ribonucleoprotein complex to drive the brown/beige adipocyte thermogenic program [#7] and recruits the m6A demethylase ALKBH5 to IL6 mRNA to limit its nuclear export [#8]. In cancer contexts it directly represses c-Jun to maintain adult hepatocyte identity and restrain HCC initiation [#10], activates the glycolytic genes LDHA and ADPGK [#11, #16], suppresses the lncRNA H19 to limit hepatic lipogenesis [#12], and restricts breast cancer EMT by repressing WNT and TGF\\u03b2 programs [#14]. Its protein level and activity are tuned post-translationally by SUMOylation, which stabilizes its transcriptional activity [#11], and by NEDD4-mediated ubiquitination at K450, which targets it for proteasomal degradation [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established ZBTB7B as a sequence-specific DNA-binding transcription factor for GC-rich elements and localized its functional domains, defining the molecular basis of its transcriptional activity.\",\n      \"evidence\": \"EMSA, reporter assays, and structure-function mutagenesis on collagen alpha1(I)/alpha2(I) promoters\",\n      \"pmids\": [\"8702912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether the factor activates or represses in physiological context\", \"No genome-wide binding map\", \"Endogenous target repertoire unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed ZBTB7B functions as a repressor of multiple ECM genes and dimerizes through its POZ and zinc-finger regions, framing it as a multimeric transcriptional regulator of matrix gene expression.\",\n      \"evidence\": \"Reporter assays, EMSA, and co-immunoprecipitation of hcKrox isoforms\",\n      \"pmids\": [\"11691585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dimer composition in vivo not defined\", \"Single lab\", \"Cofactors mediating repression not identified at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how ZBTB7B represses COL1A1 by binding the proximal promoter and recruiting NF-\\u03baB p65 via Sp1/Sp3, establishing a protein-interaction-based mechanism for matrix gene repression.\",\n      \"evidence\": \"ChIP, re-ChIP, co-IP, siRNA knockdown, and reporter assays in scleroderma fibroblasts\",\n      \"pmids\": [\"22139845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the multiprotein complex unresolved\", \"Generality beyond collagen promoters not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the developmental logic by which ZBTB7B drives CD4 T cell commitment, showing it antagonizes Runx-mediated CD4 repression through an HDAC-sensitive transcriptional mechanism.\",\n      \"evidence\": \"In vitro reporter assays, in vivo mouse genetics, HDAC inhibitor treatment, and domain-function analysis across Runx1/Runx3\",\n      \"pmids\": [\"17878336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct targets cooperating with Runx not fully enumerated\", \"Precise chromatin mechanism of antagonism unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that the BTB-POZ domain is required for ZBTB7B control of NKT effector subset balance, linking a specific domain to in vivo lineage and cytokine outcomes.\",\n      \"evidence\": \"BTB-POZ domain missense mutant mouse, flow cytometry, and cytokine profiling\",\n      \"pmids\": [\"23105140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners engaged by the BTB-POZ domain in NKT cells not identified\", \"Target genes driving the IL-17 vs IFN-\\u03b3 switch not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended ZBTB7B function beyond classical transcription by showing it recruits a Blnc1/hnRNPU ribonucleoprotein complex to activate the thermogenic gene program in brown/beige fat.\",\n      \"evidence\": \"Genome-wide screen, knockout mice, proteomic identification of partners, and cold-challenge phenotyping\",\n      \"pmids\": [\"28784777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the lncRNP complex is targeted to thermogenic loci is unresolved\", \"Direct DNA-binding contribution vs RNP scaffolding not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a post-transcriptional role in which ZBTB7B recruits ALKBH5 to demethylate IL6 mRNA and block its nuclear export, implicating it in m6A-dependent RNA regulation.\",\n      \"evidence\": \"siRNA knockdown, RNA co-IP, m6A quantification, and nuclear export assays\",\n      \"pmids\": [\"32828308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single study\", \"Direct vs indirect ZBTB7B-ALKBH5-mRNA recruitment not structurally defined\", \"Breadth of mRNA targets unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Pinpointed the first zinc finger as the determinant of DNA recognition and provided a genome-wide map of ThPOK chromatin occupancy in T cell lineage specification.\",\n      \"evidence\": \"ENU mutagenesis (R367Q), structural prediction, ChIP-seq, and in vivo immune phenotyping\",\n      \"pmids\": [\"31792077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full target network not functionally validated\", \"Cofactor composition at occupied sites not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established ZBTB7B as a guardian of adult hepatocyte identity that directly represses and competes with c-Jun, restraining HCC initiation.\",\n      \"evidence\": \"Hepatocyte-specific knockout, multi-omics (transcriptomic, phosphoproteomic, ChIP-seq), reporter assays, and c-Jun knockdown rescue\",\n      \"pmids\": [\"38225233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of chromatin competition with c-Jun not structurally defined\", \"Upstream signals controlling ZBTB7B in liver unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked ZBTB7B to glycolytic and lipid metabolic control in cancer, showing it activates LDHA (stabilized by SUMOylation) and suppresses lncRNA H19 to limit hepatic lipogenesis.\",\n      \"evidence\": \"Luciferase reporter, ChIP-qPCR, RNA-seq, SUMOylation assay, and liver-specific knockout metabolic phenotyping\",\n      \"pmids\": [\"39107297\", \"39714087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMOylation site and machinery not mapped\", \"Mechanism of H19 suppression not detailed\", \"Single lab per study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed ZBTB7B physically engages the androgen receptor NTD and restricts AR-driven and EMT programs, broadening its repressive role to additional cancer contexts.\",\n      \"evidence\": \"Co-IP, immunofluorescence, cycloheximide chase, ubiquitination assays, domain mapping; and super-enhancer profiling with ThPOK manipulation in breast cancer lines\",\n      \"pmids\": [\"41378003\", \"41231242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AR effects are transcriptional vs stability-based not fully separated\", \"Direct DNA targets in EMT repression not mapped\", \"Single lab per study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined post-translational control of ZBTB7B stability by NEDD4-mediated K450 ubiquitination and linked ZBTB7B to activation of metabolic (ADPGK, GPR17) and immune-infiltration (CXCL10) programs in tumors.\",\n      \"evidence\": \"Reporter assays, ChIP, co-IP, site-specific ubiquitination mutagenesis (K450), lentiviral overexpression, and in vitro/xenograft tumor models\",\n      \"pmids\": [\"41807371\", \"41294275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of GPR17/CXCL10 transcriptional activation not fully elaborated\", \"Signals regulating NEDD4-ZBTB7B in vivo unclear\", \"Single lab per study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZBTB7B switches between activator, repressor, and RNA/m6A-regulatory modes across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking cofactor selection to activation vs repression\", \"Structural basis of partner choice (Sp1/Sp3, p65, hnRNPU, ALKBH5, AR) unknown\", \"Integration of SUMO and NEDD4 post-translational control with context-specific outputs undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 4, 5, 10, 11, 16]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 5, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 11, 12, 16]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 14, 15]}\n    ],\n    \"complexes\": [\n      \"Blnc1/hnRNPU ribonucleoprotein complex\"\n    ],\n    \"partners\": [\n      \"SP1\",\n      \"SP3\",\n      \"RELA\",\n      \"HNRNPU\",\n      \"ALKBH5\",\n      \"AR\",\n      \"NEDD4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}