{"gene":"ZBTB7B","run_date":"2026-04-28T23:00:24","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; the transactivation domain maps to the zinc finger and C-terminal domains, and the dimerization domain maps to the C-terminal end of the protein.","method":"Electrophoretic mobility shift assay (EMSA), transient transfection/reporter assays, structure-function deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assays plus domain mutagenesis/deletion in a single rigorous 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 by DNase footprinting, EMSA, and recombinant c-Krox protein expressed in COS cells.","method":"DNase footprinting, EMSA, recombinant protein expression","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro binding confirmed with recombinant protein, single lab","pmids":["9421237"],"is_preprint":false},{"year":2001,"finding":"ZBTB7B (hcKrox-alpha) suppresses transcription of fibronectin and alpha1(I) collagen promoters, and forms homo- and heterodimers with related hcKrox family members via the N-terminal POZ domain and zinc-finger region.","method":"Transient transfection, stable cell lines, EMSA, co-immunoprecipitation","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP plus functional reporter assays, single lab","pmids":["11691585"],"is_preprint":false},{"year":2005,"finding":"c-Krox (ZBTB7B) down-regulates UDP-glucose dehydrogenase (UDPGD) gene expression in chondrocytes by acting on a cis-sequence (+18 to +39 bp) that also binds Sp1/Sp3, inhibiting glycosaminoglycan synthesis.","method":"Transient transfection, decoy oligonucleotide experiments, radiosulfate incorporation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — functional reporter assay with decoy oligonucleotides and metabolic readout, single lab","pmids":["15982635"],"is_preprint":false},{"year":2007,"finding":"ZBTB7B promotes CD4 expression by antagonizing Runx3- and Runx1-mediated transcriptional repression of the CD4 silencer; this antagonism requires domains of ZBTB7B essential for CD4 lineage commitment in vivo, and is abrogated by histone deacetylase inhibitors, suggesting ZBTB7B reduces expression of co-repressors that cooperate with Runx.","method":"In vitro transcriptional reporter assays, in vivo genetic rescue experiments, HDAC inhibitor treatment","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (in vitro and in vivo), strong genetic epistasis data","pmids":["17878336"],"is_preprint":false},{"year":2008,"finding":"c-Krox (ZBTB7B) acts through the -112/-61 bp region of the COL1A1 promoter together with Sp1 to mediate inhibition of COL1A1 transcription by chondroitin sulfate in fibroblasts.","method":"Transient transfection, reporter assay","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 — single lab, reporter assay without direct binding confirmation for this context","pmids":["18298657"],"is_preprint":false},{"year":2011,"finding":"c-Krox (ZBTB7B) physically interacts with Sp1, Sp3, and the p65 subunit of NF-κB on the COL1A1 proximal promoter; NF-κB inhibits COL1A1 transcription by being recruited through these protein interactions, and knockdown of c-Krox prevents the p65 inhibitory effect in scleroderma fibroblasts.","method":"Co-immunoprecipitation, ChIP, re-ChIP, siRNA knockdown, reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP validated by re-ChIP and siRNA functional rescue, multiple orthogonal methods","pmids":["22139845"],"is_preprint":false},{"year":2012,"finding":"ZBTB7B is required for normal NKT cell subset development; a missense mutation in the BTB-POZ domain causes NKT cells to lose CD4, gain CD8, become RORγt-positive, and overproduce IL-17 while losing IFN-γ production, demonstrating that ZBTB7B genetically determines effector subset balance in NKT cells.","method":"Mouse genetic model (helpless missense mutation), flow cytometry, cytokine analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — clean genetic model with defined cellular and cytokine phenotypes, replicated across heterozygous and homozygous animals","pmids":["23105140"],"is_preprint":false},{"year":2017,"finding":"Zbtb7b drives brown and beige fat thermogenesis by recruiting the Blnc1/hnRNPU ribonucleoprotein complex to activate thermogenic gene expression; genetic ablation of Zbtb7b impairs cold-induced transcriptional remodeling in brown fat and reduces inguinal white fat browning.","method":"Genome-wide functional screen, proteomic analysis, genetic knockout mouse model, cold challenge","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — proteomic identification of complex plus in vivo KO phenotype with transcriptional readout, multiple methods","pmids":["28784777"],"is_preprint":false},{"year":2020,"finding":"ZBTB7B suppresses radiation-induced IL-6 production by recruiting the RNA demethylase ALKBH5 to IL6 mRNA, leading to demethylation of N6-methyladenosine (m6A) on IL6 mRNA and inhibiting its nuclear export.","method":"siRNA knockdown, m6A modification assay, nuclear export assay, co-immunoprecipitation of ZBTB7B with ALKBH5","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway (RNA demethylation and nuclear export) supported by co-IP and functional knockdown, single lab","pmids":["32828308"],"is_preprint":false},{"year":2020,"finding":"An R367Q mutation in the first DNA-binding zinc finger domain of ZBTB7B causes loss of base contact in the major groove of DNA, impairing DNA binding; ChIP-seq of ThPOK-containing chromatin complexes identified transcriptional networks controlling CD4+CD8+ T cell development.","method":"ENU mutagenesis screen, structural modeling, ChIP-seq","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq with structural prediction of DNA-contact loss, in vivo genetic model","pmids":["31792077"],"is_preprint":false},{"year":2024,"finding":"ZBTB7B directly represses c-Jun expression and competes with c-Jun for chromatin binding in hepatocytes; hepatocyte-specific ZBTB7B knockout accelerates HCC initiation in an Akt/N-Ras oncogene model, and this is rescued by c-Jun knockdown or dominant-negative c-Jun.","method":"Hepatocyte-specific knockout mouse, ChIP-seq, transcriptomics, phosphoproteomics, genetic rescue with c-Jun knockdown/dominant negative","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — integrated multi-omics (ChIP-seq, transcriptomics, phosphoproteomics) plus in vivo genetic rescue, single lab with multiple orthogonal methods","pmids":["38225233"],"is_preprint":false},{"year":2024,"finding":"ZBTB7B transcriptionally activates LDHA promoter (a rate-limiting glycolytic enzyme gene); its transcriptional activity is stabilized by SUMOylation, and ALDH1A1 acts upstream to regulate ZBTB7B levels.","method":"Luciferase reporter assay, ChIP-qPCR, RNA-seq, western blot, SUMOylation assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding confirmed by ChIP-qPCR and reporter assay, SUMOylation modification identified, single lab","pmids":["39107297"],"is_preprint":false},{"year":2024,"finding":"Zbtb7b suppresses the lncRNA H19 to attenuate hepatic de novo lipogenesis and increase fatty acid oxidation, thereby preventing lipid accumulation in MASLD-associated hepatocytes.","method":"Liver-specific knockout mouse model, gene expression analysis","journal":"Physiological reports","confidence":"Low","confidence_rationale":"Tier 3 — genetic knockout with metabolic phenotype but limited direct mechanistic validation of H19 binding/regulation","pmids":["39714087"],"is_preprint":false},{"year":2025,"finding":"ZBTB7B physically binds the androgen receptor (AR) via the AR N-terminal domain (NTD), promotes AR nuclear translocation and stability, and its depletion leads to AR ubiquitination and proteasomal degradation in LNCaP prostate cancer cells.","method":"Co-immunoprecipitation, immunofluorescence colocalization, cycloheximide chase, ubiquitination assay, domain-mapping with NTD/DBD/LBD constructs, siRNA knockdown","journal":"Translational cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP plus domain mapping plus functional ubiquitination/stability assays, single lab","pmids":["41378003"],"is_preprint":false},{"year":2025,"finding":"ZBTB7B transcriptionally activates GPR17 expression in glioma cells, which suppresses protein kinase A phosphorylation, amplifies mitochondrial ROS generation, and triggers Caspase3-dependent apoptosis; ZBTB7B also upregulates CXCL10 secretion to enhance CD4+ and CD8+ T cell accumulation.","method":"Lentiviral overexpression, in vitro functional assays, xenograft assays, tissue microarray with multiplex immunofluorescence","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — overexpression with defined pathway readouts (PKA, ROS, Caspase3, CXCL10) in vitro and in vivo, single lab","pmids":["41294275"],"is_preprint":false},{"year":2025,"finding":"ZBTB7B restricts breast cancer cells to a luminal, non-migratory epithelial phenotype by suppressing expression of EMT-related genes, WNT/β-catenin target genes, and the pro-metastatic TGFβ pathway; ThPOK expression is highest in luminal breast cancer and is driven by a super-enhancer.","method":"Super-enhancer profiling, master regulator activity inference, ThPOK level manipulation in cell lines, gene expression analysis","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — SE profiling combined with functional gain/loss-of-function experiments showing defined transcriptional pathway suppression, single lab","pmids":["41231242"],"is_preprint":false},{"year":2026,"finding":"ZBTB7B is a transcriptional activator of ADPGK (a non-canonical glycolytic enzyme) in lung adenocarcinoma; the E3 ubiquitin ligase NEDD4 directly interacts with ZBTB7B, mediating its ubiquitination at K450 and proteasomal degradation, thereby suppressing ADPGK expression and glycolysis.","method":"Transcription reporter assay, ChIP, co-immunoprecipitation, ubiquitination assay with K450 site-specific mutagenesis, in vitro and in vivo tumor models","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 1-2 — specific ubiquitination site identified by mutagenesis, direct NEDD4 interaction confirmed by co-IP, functional rescue in vivo, multiple orthogonal methods","pmids":["41807371"],"is_preprint":false}],"current_model":"ZBTB7B (ThPOK/c-Krox) is a zinc finger-BTB domain transcription factor that directly binds GC-rich DNA sequences through its zinc finger domains (dimerized via the POZ/BTB domain) to activate or repress target genes including collagens, UDPGD, c-Jun, LDHA, ADPGK, GPR17, and CXCL10; in T cell development it antagonizes Runx-mediated CD4 silencing and controls NKT cell subset fate; in adipocytes it recruits the Blnc1/hnRNPU lncRNA–ribonucleoprotein complex to drive thermogenic gene expression; it post-translationally regulates the androgen receptor by binding its NTD to prevent ubiquitination/degradation; and it is itself subject to NEDD4-mediated ubiquitination at K450 and SUMOylation-dependent stabilization, while also recruiting the RNA demethylase ALKBH5 to m6A-modify IL6 mRNA and inhibit its nuclear export."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing ZBTB7B as a sequence-specific transcription factor: the zinc finger and C-terminal domains were mapped as the transactivation region, and the protein was shown to bind multiple GC-rich elements in collagen gene promoters, defining its basic molecular architecture.","evidence":"EMSA, reporter assays, and deletion mutagenesis on mouse collagen promoters","pmids":["8702912"],"confidence":"High","gaps":["Crystal structure of DNA–zinc finger complex not resolved","In vivo relevance of collagen regulation not tested"]},{"year":2001,"claim":"The BTB/POZ domain was identified as a dimerization interface enabling homo- and heterodimerization, and ZBTB7B was shown to also function as a transcriptional repressor of extracellular matrix genes, expanding its role beyond activation.","evidence":"Co-immunoprecipitation, EMSA, and reporter assays in stable cell lines","pmids":["11691585"],"confidence":"Medium","gaps":["Identity of heterodimerization partners and their functional significance unclear","Repression mechanism (corepressor recruitment) not defined"]},{"year":2007,"claim":"ZBTB7B was placed at the center of CD4+ T cell lineage commitment by demonstrating that it antagonizes Runx-mediated CD4 silencer activity; this required specific ZBTB7B domains and was sensitive to HDAC inhibition, indicating an epigenetic mechanism.","evidence":"Reporter assays, in vivo genetic rescue in T cell development, HDAC inhibitor treatment","pmids":["17878336"],"confidence":"High","gaps":["Identity of the corepressor(s) whose expression ZBTB7B reduces was not determined","Direct chromatin occupancy at the CD4 silencer not shown by ChIP"]},{"year":2011,"claim":"A ternary complex mechanism was established in which ZBTB7B physically bridges Sp1/Sp3 and NF-κB p65 on the COL1A1 promoter, explaining how NF-κB represses collagen transcription without direct DNA binding at this locus.","evidence":"Co-IP, sequential ChIP (re-ChIP), siRNA knockdown, reporter assays in scleroderma fibroblasts","pmids":["22139845"],"confidence":"High","gaps":["Structural basis of the ternary complex not resolved","Whether this bridging mechanism operates genome-wide or is promoter-specific"]},{"year":2012,"claim":"ZBTB7B was shown to genetically determine NKT cell effector subset identity: a BTB-domain missense mutation shifted NKT cells from CD4+IFN-γ+ to CD8+IL-17+ RORγt+ fate, revealing a lineage-specifying function beyond conventional T cells.","evidence":"ENU-derived mouse mutant (helpless), flow cytometry, cytokine profiling","pmids":["23105140"],"confidence":"High","gaps":["Direct transcriptional targets controlling NKT subset fate not identified","Whether the BTB domain mutation disrupts dimerization or corepressor interaction unresolved"]},{"year":2017,"claim":"ZBTB7B was discovered to function as a metabolic regulator by recruiting the Blnc1/hnRNPU lncRNA–ribonucleoprotein complex to thermogenic gene promoters, demonstrating a non-classical transcriptional activation mechanism involving lncRNA scaffolding.","evidence":"Genome-wide functional screen, proteomics, Zbtb7b knockout mice with cold challenge","pmids":["28784777"],"confidence":"High","gaps":["Whether ZBTB7B directly binds Blnc1 RNA or contacts it through hnRNPU not resolved","Genome-wide map of Blnc1-dependent vs. -independent ZBTB7B target genes not provided"]},{"year":2020,"claim":"Two studies expanded the mechanistic repertoire: an R367Q zinc finger mutation confirmed the structural basis for DNA contact in the major groove and enabled ChIP-seq mapping of ThPOK-bound loci in T cell development, while a separate study revealed a post-transcriptional role in which ZBTB7B recruits the m6A demethylase ALKBH5 to IL6 mRNA, inhibiting its nuclear export after irradiation.","evidence":"ENU mutagenesis with structural modeling and ChIP-seq (PMID:31792077); siRNA knockdown, m6A assay, co-IP of ZBTB7B–ALKBH5 (PMID:32828308)","pmids":["31792077","32828308"],"confidence":"Medium","gaps":["Crystal structure of zinc finger–DNA complex still lacking","Whether ALKBH5 recruitment depends on ZBTB7B's BTB or zinc finger domain not tested","Single-lab validation of the RNA regulatory mechanism"]},{"year":2024,"claim":"Multi-omic studies established ZBTB7B as a hepatic tumor suppressor that directly represses c-Jun and competes for its chromatin targets; separately, ZBTB7B was shown to transcriptionally activate LDHA with SUMOylation stabilizing ZBTB7B protein, revealing a post-translational regulatory axis.","evidence":"Hepatocyte-specific KO, ChIP-seq, transcriptomics, phosphoproteomics, genetic rescue (PMID:38225233); ChIP-qPCR, reporter assay, SUMOylation assay (PMID:39107297)","pmids":["38225233","39107297"],"confidence":"High","gaps":["SUMOylation site(s) on ZBTB7B not mapped","How ZBTB7B competition with c-Jun at chromatin is resolved structurally unknown","Whether hepatic tumor suppression is c-Jun-exclusive or involves additional targets"]},{"year":2025,"claim":"ZBTB7B's post-translational regulation was further defined: NEDD4 was identified as the E3 ligase that ubiquitinates ZBTB7B at K450 for proteasomal degradation; independently, ZBTB7B was shown to stabilize the androgen receptor by binding its NTD and preventing AR ubiquitination, and to enforce the luminal epithelial phenotype in breast cancer by suppressing EMT/WNT/TGFβ programs.","evidence":"K450 mutagenesis, co-IP, in vivo tumor models (PMID:41807371); AR domain mapping, cycloheximide chase, ubiquitination assay (PMID:41378003); super-enhancer profiling and gain/loss-of-function in breast cancer lines (PMID:41231242)","pmids":["41807371","41378003","41231242"],"confidence":"Medium","gaps":["NEDD4–ZBTB7B interaction surface not structurally defined","AR stabilization mechanism in vivo not validated","Whether luminal phenotype enforcement is direct transcriptional repression or indirect"]},{"year":null,"claim":"Key unresolved questions include the structural basis of ZBTB7B's zinc finger–DNA interaction, the identity of corepressors through which it antagonizes Runx, the interplay between SUMOylation and NEDD4-mediated ubiquitination in controlling ZBTB7B stability, and how its RNA-regulatory function via ALKBH5 relates to its canonical transcriptional activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure available","Corepressor identity downstream of Runx antagonism unknown","Cross-talk between SUMOylation and K450 ubiquitination unexplored","Genome-wide scope of m6A-regulatory function undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,2,10,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,4,6,8,11,12,15,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,10,11,14]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,4,6,11,12,15,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,7,10,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,12,13,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[14,17]}],"complexes":["Blnc1/hnRNPU ribonucleoprotein complex"],"partners":["ALKBH5","NEDD4","AR","RELA","SP1","SP3","HNRNPU","RUNX3"],"other_free_text":[]},"mechanistic_narrative":"ZBTB7B (ThPOK/c-Krox) is a BTB/POZ-zinc finger transcription factor that binds GC-rich DNA sequences to activate or repress diverse target genes, functioning as a lineage-specifying regulator in T cell and NKT cell development, a metabolic transcriptional switch in adipose tissue and liver, and a context-dependent tumor suppressor or oncogenic cofactor. Its zinc finger domains mediate direct DNA contact at promoters of collagen genes, LDHA, ADPGK, GPR17, and c-Jun, while the BTB/POZ domain enables homodimerization and heterodimerization and is essential for antagonizing Runx-mediated CD4 silencing during CD4+ T cell commitment and for controlling NKT cell effector subset balance [PMID:8702912, PMID:17878336, PMID:23105140, PMID:31792077]. Beyond classical transcription, ZBTB7B recruits the lncRNA–ribonucleoprotein complex Blnc1/hnRNPU to drive thermogenic gene expression in brown and beige fat, recruits the m6A demethylase ALKBH5 to regulate IL6 mRNA nuclear export, and stabilizes the androgen receptor by binding its N-terminal domain to prevent ubiquitination [PMID:28784777, PMID:32828308, PMID:41378003]. ZBTB7B protein levels are themselves regulated by NEDD4-mediated ubiquitination at K450 leading to proteasomal degradation and by SUMOylation-dependent stabilization [PMID:41807371, PMID:39107297]."},"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":54,"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":38,"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":22,"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":21,"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":"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":14,"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":7,"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":7,"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":5,"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":3,"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":"41294275","id":"PMC_41294275","title":"ZBTB7B inhibits glioma tumorigenicity by upregulating GPR17 and CXCL10.","date":"2025","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":"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":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":14136,"output_tokens":4099,"usd":0.051946},"stage2":{"model":"claude-opus-4-6","input_tokens":7577,"output_tokens":2981,"usd":0.168615},"total_usd":0.220561,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","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; the transactivation domain maps to the zinc finger and C-terminal domains, and the dimerization domain maps to the C-terminal end of the protein.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), transient transfection/reporter assays, structure-function deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assays plus domain mutagenesis/deletion in a single rigorous 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 by DNase footprinting, EMSA, and recombinant c-Krox protein expressed in COS cells.\",\n      \"method\": \"DNase footprinting, EMSA, recombinant protein expression\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding confirmed with recombinant protein, single lab\",\n      \"pmids\": [\"9421237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ZBTB7B (hcKrox-alpha) suppresses transcription of fibronectin and alpha1(I) collagen promoters, and forms homo- and heterodimers with related hcKrox family members via the N-terminal POZ domain and zinc-finger region.\",\n      \"method\": \"Transient transfection, stable cell lines, EMSA, co-immunoprecipitation\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus functional reporter assays, single lab\",\n      \"pmids\": [\"11691585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Krox (ZBTB7B) down-regulates UDP-glucose dehydrogenase (UDPGD) gene expression in chondrocytes by acting on a cis-sequence (+18 to +39 bp) that also binds Sp1/Sp3, inhibiting glycosaminoglycan synthesis.\",\n      \"method\": \"Transient transfection, decoy oligonucleotide experiments, radiosulfate incorporation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reporter assay with decoy oligonucleotides and metabolic readout, single lab\",\n      \"pmids\": [\"15982635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ZBTB7B promotes CD4 expression by antagonizing Runx3- and Runx1-mediated transcriptional repression of the CD4 silencer; this antagonism requires domains of ZBTB7B essential for CD4 lineage commitment in vivo, and is abrogated by histone deacetylase inhibitors, suggesting ZBTB7B reduces expression of co-repressors that cooperate with Runx.\",\n      \"method\": \"In vitro transcriptional reporter assays, in vivo genetic rescue experiments, HDAC inhibitor treatment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vitro and in vivo), strong genetic epistasis data\",\n      \"pmids\": [\"17878336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"c-Krox (ZBTB7B) acts through the -112/-61 bp region of the COL1A1 promoter together with Sp1 to mediate inhibition of COL1A1 transcription by chondroitin sulfate in fibroblasts.\",\n      \"method\": \"Transient transfection, reporter assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, reporter assay without direct binding confirmation for this context\",\n      \"pmids\": [\"18298657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"c-Krox (ZBTB7B) physically interacts with Sp1, Sp3, and the p65 subunit of NF-κB on the COL1A1 proximal promoter; NF-κB inhibits COL1A1 transcription by being recruited through these protein interactions, and knockdown of c-Krox prevents the p65 inhibitory effect in scleroderma fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, re-ChIP, siRNA knockdown, reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP validated by re-ChIP and siRNA functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"22139845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZBTB7B is required for normal NKT cell subset development; a missense mutation in the BTB-POZ domain causes NKT cells to lose CD4, gain CD8, become RORγt-positive, and overproduce IL-17 while losing IFN-γ production, demonstrating that ZBTB7B genetically determines effector subset balance in NKT cells.\",\n      \"method\": \"Mouse genetic model (helpless missense mutation), flow cytometry, cytokine analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic model with defined cellular and cytokine phenotypes, replicated across heterozygous and homozygous animals\",\n      \"pmids\": [\"23105140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Zbtb7b drives brown and beige fat thermogenesis by recruiting the Blnc1/hnRNPU ribonucleoprotein complex to activate thermogenic gene expression; genetic ablation of Zbtb7b impairs cold-induced transcriptional remodeling in brown fat and reduces inguinal white fat browning.\",\n      \"method\": \"Genome-wide functional screen, proteomic analysis, genetic knockout mouse model, cold challenge\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomic identification of complex plus in vivo KO phenotype with transcriptional readout, multiple methods\",\n      \"pmids\": [\"28784777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZBTB7B suppresses radiation-induced IL-6 production by recruiting the RNA demethylase ALKBH5 to IL6 mRNA, leading to demethylation of N6-methyladenosine (m6A) on IL6 mRNA and inhibiting its nuclear export.\",\n      \"method\": \"siRNA knockdown, m6A modification assay, nuclear export assay, co-immunoprecipitation of ZBTB7B with ALKBH5\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (RNA demethylation and nuclear export) supported by co-IP and functional knockdown, single lab\",\n      \"pmids\": [\"32828308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"An R367Q mutation in the first DNA-binding zinc finger domain of ZBTB7B causes loss of base contact in the major groove of DNA, impairing DNA binding; ChIP-seq of ThPOK-containing chromatin complexes identified transcriptional networks controlling CD4+CD8+ T cell development.\",\n      \"method\": \"ENU mutagenesis screen, structural modeling, ChIP-seq\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq with structural prediction of DNA-contact loss, in vivo genetic model\",\n      \"pmids\": [\"31792077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZBTB7B directly represses c-Jun expression and competes with c-Jun for chromatin binding in hepatocytes; hepatocyte-specific ZBTB7B knockout accelerates HCC initiation in an Akt/N-Ras oncogene model, and this is rescued by c-Jun knockdown or dominant-negative c-Jun.\",\n      \"method\": \"Hepatocyte-specific knockout mouse, ChIP-seq, transcriptomics, phosphoproteomics, genetic rescue with c-Jun knockdown/dominant negative\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — integrated multi-omics (ChIP-seq, transcriptomics, phosphoproteomics) plus in vivo genetic rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38225233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZBTB7B transcriptionally activates LDHA promoter (a rate-limiting glycolytic enzyme gene); its transcriptional activity is stabilized by SUMOylation, and ALDH1A1 acts upstream to regulate ZBTB7B levels.\",\n      \"method\": \"Luciferase reporter assay, ChIP-qPCR, RNA-seq, western blot, SUMOylation assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding confirmed by ChIP-qPCR and reporter assay, SUMOylation modification identified, single lab\",\n      \"pmids\": [\"39107297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Zbtb7b suppresses the lncRNA H19 to attenuate hepatic de novo lipogenesis and increase fatty acid oxidation, thereby preventing lipid accumulation in MASLD-associated hepatocytes.\",\n      \"method\": \"Liver-specific knockout mouse model, gene expression analysis\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic knockout with metabolic phenotype but limited direct mechanistic validation of H19 binding/regulation\",\n      \"pmids\": [\"39714087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZBTB7B physically binds the androgen receptor (AR) via the AR N-terminal domain (NTD), promotes AR nuclear translocation and stability, and its depletion leads to AR ubiquitination and proteasomal degradation in LNCaP prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, cycloheximide chase, ubiquitination assay, domain-mapping with NTD/DBD/LBD constructs, siRNA knockdown\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus domain mapping plus functional ubiquitination/stability assays, single lab\",\n      \"pmids\": [\"41378003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZBTB7B transcriptionally activates GPR17 expression in glioma cells, which suppresses protein kinase A phosphorylation, amplifies mitochondrial ROS generation, and triggers Caspase3-dependent apoptosis; ZBTB7B also upregulates CXCL10 secretion to enhance CD4+ and CD8+ T cell accumulation.\",\n      \"method\": \"Lentiviral overexpression, in vitro functional assays, xenograft assays, tissue microarray with multiplex immunofluorescence\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — overexpression with defined pathway readouts (PKA, ROS, Caspase3, CXCL10) in vitro and in vivo, single lab\",\n      \"pmids\": [\"41294275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZBTB7B restricts breast cancer cells to a luminal, non-migratory epithelial phenotype by suppressing expression of EMT-related genes, WNT/β-catenin target genes, and the pro-metastatic TGFβ pathway; ThPOK expression is highest in luminal breast cancer and is driven by a super-enhancer.\",\n      \"method\": \"Super-enhancer profiling, master regulator activity inference, ThPOK level manipulation in cell lines, gene expression analysis\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — SE profiling combined with functional gain/loss-of-function experiments showing defined transcriptional pathway suppression, single lab\",\n      \"pmids\": [\"41231242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZBTB7B is a transcriptional activator of ADPGK (a non-canonical glycolytic enzyme) in lung adenocarcinoma; the E3 ubiquitin ligase NEDD4 directly interacts with ZBTB7B, mediating its ubiquitination at K450 and proteasomal degradation, thereby suppressing ADPGK expression and glycolysis.\",\n      \"method\": \"Transcription reporter assay, ChIP, co-immunoprecipitation, ubiquitination assay with K450 site-specific mutagenesis, in vitro and in vivo tumor models\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — specific ubiquitination site identified by mutagenesis, direct NEDD4 interaction confirmed by co-IP, functional rescue in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"41807371\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZBTB7B (ThPOK/c-Krox) is a zinc finger-BTB domain transcription factor that directly binds GC-rich DNA sequences through its zinc finger domains (dimerized via the POZ/BTB domain) to activate or repress target genes including collagens, UDPGD, c-Jun, LDHA, ADPGK, GPR17, and CXCL10; in T cell development it antagonizes Runx-mediated CD4 silencing and controls NKT cell subset fate; in adipocytes it recruits the Blnc1/hnRNPU lncRNA–ribonucleoprotein complex to drive thermogenic gene expression; it post-translationally regulates the androgen receptor by binding its NTD to prevent ubiquitination/degradation; and it is itself subject to NEDD4-mediated ubiquitination at K450 and SUMOylation-dependent stabilization, while also recruiting the RNA demethylase ALKBH5 to m6A-modify IL6 mRNA and inhibit its nuclear export.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZBTB7B (ThPOK/c-Krox) is a BTB/POZ-zinc finger transcription factor that binds GC-rich DNA sequences to activate or repress diverse target genes, functioning as a lineage-specifying regulator in T cell and NKT cell development, a metabolic transcriptional switch in adipose tissue and liver, and a context-dependent tumor suppressor or oncogenic cofactor. Its zinc finger domains mediate direct DNA contact at promoters of collagen genes, LDHA, ADPGK, GPR17, and c-Jun, while the BTB/POZ domain enables homodimerization and heterodimerization and is essential for antagonizing Runx-mediated CD4 silencing during CD4+ T cell commitment and for controlling NKT cell effector subset balance [PMID:8702912, PMID:17878336, PMID:23105140, PMID:31792077]. Beyond classical transcription, ZBTB7B recruits the lncRNA–ribonucleoprotein complex Blnc1/hnRNPU to drive thermogenic gene expression in brown and beige fat, recruits the m6A demethylase ALKBH5 to regulate IL6 mRNA nuclear export, and stabilizes the androgen receptor by binding its N-terminal domain to prevent ubiquitination [PMID:28784777, PMID:32828308, PMID:41378003]. ZBTB7B protein levels are themselves regulated by NEDD4-mediated ubiquitination at K450 leading to proteasomal degradation and by SUMOylation-dependent stabilization [PMID:41807371, PMID:39107297].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing ZBTB7B as a sequence-specific transcription factor: the zinc finger and C-terminal domains were mapped as the transactivation region, and the protein was shown to bind multiple GC-rich elements in collagen gene promoters, defining its basic molecular architecture.\",\n      \"evidence\": \"EMSA, reporter assays, and deletion mutagenesis on mouse collagen promoters\",\n      \"pmids\": [\"8702912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of DNA–zinc finger complex not resolved\", \"In vivo relevance of collagen regulation not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The BTB/POZ domain was identified as a dimerization interface enabling homo- and heterodimerization, and ZBTB7B was shown to also function as a transcriptional repressor of extracellular matrix genes, expanding its role beyond activation.\",\n      \"evidence\": \"Co-immunoprecipitation, EMSA, and reporter assays in stable cell lines\",\n      \"pmids\": [\"11691585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of heterodimerization partners and their functional significance unclear\", \"Repression mechanism (corepressor recruitment) not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"ZBTB7B was placed at the center of CD4+ T cell lineage commitment by demonstrating that it antagonizes Runx-mediated CD4 silencer activity; this required specific ZBTB7B domains and was sensitive to HDAC inhibition, indicating an epigenetic mechanism.\",\n      \"evidence\": \"Reporter assays, in vivo genetic rescue in T cell development, HDAC inhibitor treatment\",\n      \"pmids\": [\"17878336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the corepressor(s) whose expression ZBTB7B reduces was not determined\", \"Direct chromatin occupancy at the CD4 silencer not shown by ChIP\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A ternary complex mechanism was established in which ZBTB7B physically bridges Sp1/Sp3 and NF-κB p65 on the COL1A1 promoter, explaining how NF-κB represses collagen transcription without direct DNA binding at this locus.\",\n      \"evidence\": \"Co-IP, sequential ChIP (re-ChIP), siRNA knockdown, reporter assays in scleroderma fibroblasts\",\n      \"pmids\": [\"22139845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ternary complex not resolved\", \"Whether this bridging mechanism operates genome-wide or is promoter-specific\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"ZBTB7B was shown to genetically determine NKT cell effector subset identity: a BTB-domain missense mutation shifted NKT cells from CD4+IFN-γ+ to CD8+IL-17+ RORγt+ fate, revealing a lineage-specifying function beyond conventional T cells.\",\n      \"evidence\": \"ENU-derived mouse mutant (helpless), flow cytometry, cytokine profiling\",\n      \"pmids\": [\"23105140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets controlling NKT subset fate not identified\", \"Whether the BTB domain mutation disrupts dimerization or corepressor interaction unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"ZBTB7B was discovered to function as a metabolic regulator by recruiting the Blnc1/hnRNPU lncRNA–ribonucleoprotein complex to thermogenic gene promoters, demonstrating a non-classical transcriptional activation mechanism involving lncRNA scaffolding.\",\n      \"evidence\": \"Genome-wide functional screen, proteomics, Zbtb7b knockout mice with cold challenge\",\n      \"pmids\": [\"28784777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ZBTB7B directly binds Blnc1 RNA or contacts it through hnRNPU not resolved\", \"Genome-wide map of Blnc1-dependent vs. -independent ZBTB7B target genes not provided\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two studies expanded the mechanistic repertoire: an R367Q zinc finger mutation confirmed the structural basis for DNA contact in the major groove and enabled ChIP-seq mapping of ThPOK-bound loci in T cell development, while a separate study revealed a post-transcriptional role in which ZBTB7B recruits the m6A demethylase ALKBH5 to IL6 mRNA, inhibiting its nuclear export after irradiation.\",\n      \"evidence\": \"ENU mutagenesis with structural modeling and ChIP-seq (PMID:31792077); siRNA knockdown, m6A assay, co-IP of ZBTB7B–ALKBH5 (PMID:32828308)\",\n      \"pmids\": [\"31792077\", \"32828308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Crystal structure of zinc finger–DNA complex still lacking\", \"Whether ALKBH5 recruitment depends on ZBTB7B's BTB or zinc finger domain not tested\", \"Single-lab validation of the RNA regulatory mechanism\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multi-omic studies established ZBTB7B as a hepatic tumor suppressor that directly represses c-Jun and competes for its chromatin targets; separately, ZBTB7B was shown to transcriptionally activate LDHA with SUMOylation stabilizing ZBTB7B protein, revealing a post-translational regulatory axis.\",\n      \"evidence\": \"Hepatocyte-specific KO, ChIP-seq, transcriptomics, phosphoproteomics, genetic rescue (PMID:38225233); ChIP-qPCR, reporter assay, SUMOylation assay (PMID:39107297)\",\n      \"pmids\": [\"38225233\", \"39107297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMOylation site(s) on ZBTB7B not mapped\", \"How ZBTB7B competition with c-Jun at chromatin is resolved structurally unknown\", \"Whether hepatic tumor suppression is c-Jun-exclusive or involves additional targets\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ZBTB7B's post-translational regulation was further defined: NEDD4 was identified as the E3 ligase that ubiquitinates ZBTB7B at K450 for proteasomal degradation; independently, ZBTB7B was shown to stabilize the androgen receptor by binding its NTD and preventing AR ubiquitination, and to enforce the luminal epithelial phenotype in breast cancer by suppressing EMT/WNT/TGFβ programs.\",\n      \"evidence\": \"K450 mutagenesis, co-IP, in vivo tumor models (PMID:41807371); AR domain mapping, cycloheximide chase, ubiquitination assay (PMID:41378003); super-enhancer profiling and gain/loss-of-function in breast cancer lines (PMID:41231242)\",\n      \"pmids\": [\"41807371\", \"41378003\", \"41231242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NEDD4–ZBTB7B interaction surface not structurally defined\", \"AR stabilization mechanism in vivo not validated\", \"Whether luminal phenotype enforcement is direct transcriptional repression or indirect\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of ZBTB7B's zinc finger–DNA interaction, the identity of corepressors through which it antagonizes Runx, the interplay between SUMOylation and NEDD4-mediated ubiquitination in controlling ZBTB7B stability, and how its RNA-regulatory function via ALKBH5 relates to its canonical transcriptional activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure available\", \"Corepressor identity downstream of Runx antagonism unknown\", \"Cross-talk between SUMOylation and K450 ubiquitination unexplored\", \"Genome-wide scope of m6A-regulatory function undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 2, 10, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 4, 6, 8, 11, 12, 15, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 10, 11, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 4, 6, 11, 12, 15, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 7, 10, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 12, 13, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [14, 17]}\n    ],\n    \"complexes\": [\n      \"Blnc1/hnRNPU ribonucleoprotein complex\"\n    ],\n    \"partners\": [\n      \"ALKBH5\",\n      \"NEDD4\",\n      \"AR\",\n      \"RELA\",\n      \"SP1\",\n      \"SP3\",\n      \"HNRNPU\",\n      \"RUNX3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}