Affinage

ZBTB7A

Zinc finger and BTB domain-containing protein 7A · UniProt O95365

Length
584 aa
Mass
61.4 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZBTB7A (also known as LRF, Pokemon, FBI-1) is a BTB/POZ-zinc finger transcriptional repressor that governs cell fate decisions in hematopoietic lineages, metabolic reprogramming, and genome integrity. It homodimerizes through its BTB domain and binds GC-rich DNA sequences (consensus G(A/G)GGG) via four C2H2 zinc fingers, repressing target genes — including ARF, p21/CDKN1A, Bim, γ-globin, and glycolytic enzymes HK2 and LDHA — by recruiting NuRD/HDAC, NCoR/SMRT/BCoR, and Sin3A/HDAC1 co-repressor complexes, which effect histone deacetylation and, in some contexts, DNA methylation-mediated silencing (PMID:15662416, PMID:18801742, PMID:23658227, PMID:26816381, PMID:37066523). In lymphoid development, ZBTB7A instructs B-cell fate by repressing Notch/Dll4 signaling and maintains CD4+ T-cell identity by restraining Runx3, while in erythropoiesis it prevents apoptosis through Bim repression and silences fetal γ-globin by binding a −200 bp promoter element — disruption of which causes hereditary persistence of fetal hemoglobin (PMID:17495164, PMID:19853566, PMID:29610478, PMID:25129370). Beyond transcription, ZBTB7A controls chromatin accessibility genome-wide to enable inducible gene regulation by other transcription factors, regulates alternative splicing of BCL-X through interaction with SAM68, and maintains genome stability via a transcription-independent role in classical NHEJ by stabilizing DNA-PKcs at double-strand breaks (PMID:29813070, PMID:24514149, PMID:26446488). Recurrent loss-of-function zinc-finger mutations in AML t(8;21) and other cancers abolish DNA binding and derepress glycolytic genes, while in PTEN-null prostate cancer ZBTB7A loss bypasses senescence through SOX9-dependent Rb downregulation, establishing ZBTB7A as a context-dependent tumor suppressor (PMID:27252013, PMID:23727861, PMID:26455326).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 Medium

    Identification of ZBTB7A as a sequence-specific DNA-binding protein that recognizes the HIV-1 IST element established its basic biochemical activity as a transcription factor binding GC-rich DNA.

    Evidence Biochemical purification and UV cross-linking to IST DNA in vitro

    PMID:9199312

    Open questions at the time
    • Endogenous genomic targets unknown
    • No cellular function demonstrated
  2. 1999 Medium

    Discovery that ZBTB7A associates with BCL-6 in vivo via both BTB and zinc-finger domains, while its BTB domain homodimerizes but does not heterodimerize with BCL-6 BTB, defined its oligomeric state and partner selectivity.

    Evidence Co-immunoprecipitation and domain-mapping interaction assays

    PMID:9927193

    Open questions at the time
    • Functional consequence of BCL-6 interaction unclear
    • No reciprocal heterodimerization exclusion validated by independent lab
  3. 2003 Medium

    Systematic characterization of ZBTB7A DNA-binding specificity revealed flexible recognition of G(A/G)GGG-containing repeats in diverse configurations, explaining its capacity to bind multiple promoters including c-fos, c-myc, and adenovirus MLP.

    Evidence EMSA with mutant DNA probes across multiple promoter sequences

    PMID:12750370

    Open questions at the time
    • No genome-wide binding map
    • In vivo relevance of each binding site not established
  4. 2005 High

    The demonstration that ZBTB7A directly represses the ARF tumor suppressor and that its overexpression drives oncogenic transformation while its loss abolishes oncogene-mediated transformation established its role as a proto-oncogene acting upstream of the ARF/p53 pathway.

    Evidence Direct promoter binding, MEF knockout transformation assays, transgenic mouse tumorigenesis

    PMID:15662416

    Open questions at the time
    • ARF-independent oncogenic mechanisms not addressed
    • Tissue specificity of oncogenic role not defined
  5. 2006 High

    The 2.1 Å crystal structure of the ZBTB7A BTB domain revealed a canonical homodimer fold with unique surface features that preclude SMRT BBD binding, distinguishing its co-repressor recruitment mechanism from BCL-6.

    Evidence X-ray crystallography with in vitro binding validation

    PMID:17189472

    Open questions at the time
    • Co-repressor binding interface on ZBTB7A BTB not structurally resolved
    • No structure of full-length protein
  6. 2007 High

    Conditional knockout revealed that ZBTB7A instructs B-cell fate by repressing Notch signaling in lymphoid progenitors, establishing its first in vivo lineage-instructive function beyond oncogenesis.

    Evidence Lymphoid-specific conditional KO mice with Notch pathway analysis

    PMID:17495164

    Open questions at the time
    • Direct Notch target gene identity not fully resolved
    • Mechanism of Notch repression (direct vs. indirect) not defined
  7. 2008 High

    Multiple studies converged to define the general co-repressor recruitment mechanism: the BTB/POZ domain recruits Sin3A/HDAC1, NCoR/SMRT, and competes with Sp1 at GC-rich promoter elements (Rb, p21), establishing HDAC-dependent histone deacetylation as the central effector mechanism.

    Evidence Co-IP, ChIP, promoter reporter assays, POZ domain mutagenesis across Rb and cell-cycle gene promoters

    PMID:18368381 PMID:18801742

    Open questions at the time
    • Selectivity among co-repressor complexes at different targets unclear
    • Genome-wide co-repressor recruitment not mapped
  8. 2009 High

    Demonstration that ZBTB7A is a GATA1 target gene essential for erythroid survival through direct Bim repression — with genetic rescue by Bim deletion — established its anti-apoptotic function in a non-lymphoid lineage.

    Evidence Lrf knockout embryos with lethal anemia rescued by Bim deletion; ChIP confirming direct repression

    PMID:19853566

    Open questions at the time
    • Additional erythroid target genes of ZBTB7A not characterized
    • Mechanism of erythroid-specific ZBTB7A regulation beyond GATA1 not defined
  9. 2012 High

    Discovery that erythroblast-specific LRF represses Dll4 to protect HSCs from aberrant Notch signals extended the Notch-repression paradigm to a cell-nonautonomous niche mechanism.

    Evidence Conditional KO mice with erythroblast-HSC crosstalk assays

    PMID:23134786

    Open questions at the time
    • Other niche-derived Notch ligands regulated by LRF not assessed
  10. 2013 High

    Two discoveries expanded ZBTB7A's mechanistic repertoire: (1) it recruits NuRD/MBD3 and BCoR to direct DNA methylation-based epigenetic silencing of p21, and (2) it antagonizes SOX9 to maintain Rb and suppress prostate cancer invasion, establishing its tumor-suppressor role in epithelial tissues.

    Evidence Co-IP with MBD3/DNMT recruitment assays; prostate-specific conditional KO with SOX9 interaction studies

    PMID:23658227 PMID:23727861

    Open questions at the time
    • Genome-wide DNA methylation changes upon ZBTB7A loss not mapped
    • SOX9-ZBTB7A structural interface unknown
  11. 2014 High

    ZBTB7A was shown to regulate alternative splicing of BCL-X via interaction with SAM68 in an HDAC-dependent manner, and to maintain CD4+ T-cell identity post-thymically by restraining Runx3, broadening its functions beyond simple transcriptional repression.

    Evidence Co-IP with SAM68 and splice-site analysis; post-thymic conditional KO with T-cell lineage tracking

    PMID:24514149 PMID:25129370

    Open questions at the time
    • Genome-wide splicing targets unknown
    • Whether splicing role is independent of promoter binding unclear
  12. 2015 High

    Two key findings: ZBTB7A maintains genome integrity through transcription-independent stabilization of DNA-PKcs at DSBs for cNHEJ, and cancer-associated zinc-finger mutations abolish DNA binding causing glycolytic derepression — linking ZBTB7A loss to metabolic reprogramming.

    Evidence DNA repair assays with DNA-PKcs co-IP; functional characterization of cancer-derived ZF mutants with glycolysis measurements

    PMID:26446488 PMID:26455326

    Open questions at the time
    • Structural basis of DNA-PKcs stabilization unknown
    • Whether glycolytic and DNA repair functions are coordinately regulated unclear
  13. 2016 High

    ChIP-seq and CRISPR KO established that ZBTB7A directly silences fetal γ-globin via NuRD recruitment and nucleosome density maintenance, independently of BCL11A, while recurrent AML t(8;21) zinc-finger mutations confirmed loss-of-function as a disease mechanism.

    Evidence ChIP-seq, CRISPR KO in erythroid cells, nucleosome occupancy assays; functional characterization of patient-derived mutations

    PMID:26816381 PMID:27252013

    Open questions at the time
    • Cooperative vs. independent action with BCL11A not fully resolved
    • In vivo AML model with ZBTB7A restoration not performed
  14. 2018 High

    Genome-wide ATAC-seq demonstrated that ZBTB7A pre-occupies promoters and enhancers to enable inducible chromatin accessibility changes by other transcription factors, redefining it as a chromatin accessibility regulator beyond a simple repressor; simultaneously, HPFH-causing mutations at the −200 bp γ-globin site were shown to disrupt ZBTB7A binding.

    Evidence ATAC-seq/ChIP-seq with CRISPR/siRNA in macrophages; EMSA and CRISPR-Cas9 editing in erythroid cells

    PMID:29610478 PMID:29813070

    Open questions at the time
    • Mechanism by which ZBTB7A pre-binding enables accessibility changes not defined
    • Whether accessibility role extends to all tissues unknown
  15. 2021 High

    Crystal structures of the four-zinc-finger DNA-binding domain bound to the γ-globin −200 element revealed that ZF1/ZF2 recognize the 5′ C:G quadruple and ZF4 contacts the 3′ C:G quadruple, providing the structural basis for HPFH mutation effects.

    Evidence X-ray crystallography of ZF1-4–DNA complex with HPFH mutant binding assays

    PMID:34592153

    Open questions at the time
    • No structure of full-length protein on DNA
    • Co-repressor complex structure on DNA not resolved
  16. 2022 High

    scRNA-seq and ChIP showed that ZBTB7A directly activates integrin β7 (Itgb7) in thymic IEL precursors to enable gut homing, extending its lymphoid functions to tissue-specific migration programs.

    Evidence Conditional KO mice with scRNA-seq, ChIP, and gut homing assays

    PMID:35354951

    Open questions at the time
    • Other gut-homing genes regulated by ZBTB7A not characterized
    • Mechanism of transcriptional activation (vs. usual repression) at this locus not explained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZBTB7A selects among its many co-repressor complexes (NuRD, NCoR/SMRT, Sin3A, BCoR) at specific loci, how its transcription-independent DNA repair function relates to its chromatin role, and the structural basis for full-length protein function on chromatin remain unresolved.
  • No full-length protein structure
  • Co-repressor selectivity mechanism unknown
  • Relationship between chromatin accessibility role and DNA repair function not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 4 R-HSA-1430728 Metabolism 3 R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1
Partners
BCL6DNA-PKCSMBD3NFKB1SAM68SMAD4SOX9SREBP1
Complex memberships
NCoR/SMRT/BCoRNuRD/HDACSin3A/HDAC1

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 ZBTB7A/Pokemon directly represses transcription of the tumor suppressor ARF gene through direct binding to its promoter, and mouse embryonic fibroblasts lacking Zbtb7a are completely refractory to oncogene-mediated cellular transformation, while Pokemon overexpression leads to oncogenic transformation in vitro and in vivo in transgenic mice. Direct promoter binding, transgenic mouse overexpression, MEF knockout transformation assays Nature High 15662416
1999 LRF/ZBTB7A protein associates in vivo with LAZ-3/BCL-6; interaction requires both the BTB/POZ domain and zinc fingers in each partner protein, and LRF BTB/POZ domain homodimerizes but does not heterodimerize with the LAZ-3/BCL-6 BTB/POZ domain alone. LRF and BCL-6 colocalize in the nucleus. Co-immunoprecipitation, in vivo interaction assays, nuclear colocalization Oncogene Medium 9927193
1997 FBI-1/ZBTB7A binds specifically to the HIV-1 inducer of short transcripts (IST) bipartite DNA element, and its binding to IST mutants correlates with IST function, suggesting FBI-1 is involved in establishing abortive transcription complexes. The protein contains at least an 86-kDa polypeptide that can be cross-linked to IST. Biochemical purification, specific DNA binding assay, UV cross-linking Molecular and cellular biology Medium 9199312
2003 FBI-1/ZBTB7A binds to inverted sequence repeats at the HIV-1 transcription start site with high flexibility, recognizing variously spaced direct, inverted, and everted repeats with consensus G(A/G)GGG(T/C)(C/T)(T/C)(C/T), and binds to sites in adenovirus 2 major late promoter, c-fos, and c-myc P1/P2 promoters. In vitro DNA binding assays with mutant probes, EMSA The Journal of biological chemistry Medium 12750370
2006 Crystal structure of the LRF/ZBTB7A BTB domain resolved to 2.1 Å shows the canonical BTB homodimer fold with novel surface features including differences in the lateral groove and charged pocket regions compared to BCL6 BTB; the 17-residue BCL6 Binding Domain (BBD) from SMRT co-repressor does not bind to the LRF BTB domain. X-ray crystallography, in vitro binding assay Protein science High 17189472
2007 LRF/ZBTB7A plays an essential role in the B versus T lymphoid cell-fate decision in mice by repressing T cell-instructive Notch signals in early lymphoid progenitors, thereby instructing them to develop into B lineage cells. Conditional knockout mice, lymphoid differentiation assays, Notch pathway analysis Science High 17495164
2008 FBI-1/ZBTB7A represses transcription of the Rb tumor suppressor gene by binding to four GC-rich promoter elements (FREs) and competing with Sp1 at GC-box 2 and FRE3; repression is mediated through the POZ domain recruiting a co-repressor-HDAC complex that deacetylates histones H3 and H4 at the Rb promoter. Promoter reporter assays, ChIP, EMSA, binding competition assays, HDAC activity assays The Journal of biological chemistry High 18801742
2008 FBI-1/ZBTB7A and SREBP-1 interact directly via their DNA binding domains and synergistically activate transcription of the FASN gene; FBI-1 alters binding patterns of Sp1 and SREBP-1 at promoter elements. Co-IP, promoter reporter assays, ChIP, EMSA The Journal of biological chemistry Medium 18682402
2009 FBI-1/ZBTB7A represses transcription of p21CIP1 by acting as a competitive transcriptional repressor of p53 and Sp1 through direct binding to proximal Sp1-3 GC-box and distal p53-responsive elements; also recruits corepressors mSin3A, NCoR, and SMRT leading to histone deacetylation. Promoter reporter assays, ChIP, competitive binding assays, co-IP The Journal of biological chemistry High 19244234
2009 LRF/ZBTB7A is a direct transcriptional target of GATA1 and plays an essential antiapoptotic role during terminal erythroid differentiation by directly repressing Bim transcription. Loss of Lrf leads to lethal anemia in embryos due to increased Bim-mediated apoptosis. Genetic Bim loss rescues the anemia phenotype of Lrf-deficient embryos. Knockout mice, genetic epistasis (Lrf/Bim double knockout), ChIP, reporter assays Developmental cell High 19853566
2005 FBI-1/ZBTB7A POZ domain interacts with the Rel homology domain of the p65 subunit of NF-κB in vivo and in vitro; FBI-1 enhances NF-κB-mediated transcription of E-selectin genes by promoting nuclear localization and stability of NF-κB/p65, and also interacts with IκBα and IκBβ. Co-IP, in vitro protein-protein interaction, confocal microscopy, reporter assays The Journal of biological chemistry Medium 15917220
2008 miR-20a post-transcriptionally regulates LRF/ZBTB7A through direct interaction with its 3'UTR, validated by gene reporter assay; LRF downregulation leads to p19ARF upregulation and senescence induction. LRF is identified as the main mediator of miR-20a-induced senescence. 3'UTR reporter assay, retroviral overexpression, comparison in LRF-null MEFs PloS one Medium 18596985
2012 LRF functions as an erythroid-specific repressor of Dll4 (Delta-like 4) expression in erythroblasts; LRF deletion in erythroblasts promotes Dll4 upregulation which sensitizes hematopoietic stem cells to T-cell instructive Notch signals in bone marrow, thereby impairing HSC maintenance. Conditional knockout mice, HSC functional assays, in vivo erythroblast-HSC crosstalk experiments Blood High 23134786
2013 ZBTB7A physically interacts with SOX9 and functionally antagonizes SOX9 transcriptional activity on target genes including MIA (involved in tumor cell invasion) and H19 (an lncRNA precursor for an RB-targeting microRNA). Inactivation of Zbtb7a leads to Rb downregulation, bypass of PTEN loss-induced cellular senescence, and invasive prostate cancer. Co-IP, conditional knockout in vivo, transcriptional reporter assays, prostate-specific deletion mouse model Nature genetics High 23727861
2013 FBI-1/ZBTB7A interacts with MBD3 in the nucleus; MBD3 is recruited to the CDKN1A promoter through interaction with FBI-1, enhancing transcriptional repression. FBI-1 recruits the Mi-2/NuRD-HDAC complex via MBD3, and also interacts with corepressors NCoR, SMRT, and BCoR. MBD3 and BCoR facilitate recruitment of DNMTs and HP1, leading to DNA methylation-based epigenetic repression of p21WAF/CDKN1A. Co-IP, ChIP, promoter reporter assays, DNMT recruitment assays Nucleic acids research High 23658227
2014 FBI-1/ZBTB7A interacts directly with the splicing factor SAM68 and reduces SAM68 binding to BCL-X mRNA, resulting in selection of the proximal 5' splice site in BCL-X exon 2 favoring anti-apoptotic BCL-XL; this splicing regulation requires histone deacetylase activity. Co-IP, RNA binding assays, alternative splicing analysis, HDAC inhibitor experiments EMBO reports High 24514149
2014 Pokemon/ZBTB7A interacts directly with Smad4 both in vitro and in vivo; overexpression decreases TGF-β-induced transcriptional activities. TGF-β1 treatment increases the Pokemon-Smad4 interaction and enhances Pokemon recruitment to Smad4-DNA complex. Pokemon recruits HDAC1 to the Smad4 complex and decreases Smad4-p300/CBP interaction, without affecting Smad2/3 activation or Smad4 DNA binding. Co-IP, in vitro pulldown, reporter assays, ChIP Biochimica et biophysica acta Medium 25514493
2014 ZBTB7A directly binds to the promoter of MCAM and transcriptionally represses its expression; downregulation of ZBTB7A results in MCAM upregulation and enhanced melanoma cell invasion and metastasis. ChIP, promoter reporter assays, invasion assays, cancer genome dataset mining Molecular cancer research Medium 25995384
2015 ZBTB7A zinc finger domain mutations found in human cancers result in loss of DNA-binding function; cancer cells harboring ZBTB7A zinc finger mutations show marked upregulation of glycolytic genes and increased glycolysis and proliferation, identifying loss-of-function zinc finger mutations as a mechanism for elevated glycolysis in cancer. Cancer genome database mining, functional characterization of mutants, glycolysis assays Oncogene Medium 26455326
2015 LRF/ZBTB7A maintains genome integrity through a transcription-independent role in the classical non-homologous end joining (cNHEJ) pathway of double-strand break repair; LRF binds and stabilizes DNA-PKcs on DSBs, thereby favoring DNA-PK activity. LRF loss results in defective cNHEJ, genomic instability, and hypersensitivity to ionizing radiation. DNA repair assays, co-IP of LRF with DNA-PKcs on DSBs, ionizing radiation sensitivity, mouse tissue analysis Nature communications High 26446488
2016 LRF/ZBTB7A occupies fetal γ-globin gene promoters and maintains nucleosome density necessary for γ-globin gene silencing in adults; LRF confers repressive activity through a NuRD repressor complex independently of BCL11A. ChIP-seq, CRISPR knockout, nucleosome occupancy assays Science High 26816381
2016 ZBTB7A mutations in AML t(8;21) patients (23% frequency) including missense and truncating mutations in the C-terminal zinc-finger domain disrupt the transcriptional repressor potential and anti-proliferative effect of ZBTB7A, demonstrating that the zinc-finger domain is required for ZBTB7A function. Functional characterization of patient-derived mutations, transcriptional reporter assays, proliferation assays Nature communications Medium 27252013
2017 KLF1 directly drives expression of ZBTB7A in erythroid cells by binding to its proximal promoter; an erythroid-specific regulation mechanism leads to upregulation of a novel ZBTB7A transcript in the erythroid compartment, placing ZBTB7A as a KLF1 target gene analogous to BCL11A. ChIP, promoter reporter assays, erythroid-specific transcript analysis Blood advances Medium 29296711
2018 BCL11A directly binds the fetal γ-globin promoter at -115 bp, and ZBTB7A directly binds at -200 bp; naturally occurring HPFH-associated point mutations at these positions disrupt repressor binding and raise γ-globin gene expression when introduced by CRISPR-Cas9 into erythroid cells. EMSA, ChIP, CRISPR-Cas9 genome editing, γ-globin expression analysis Nature genetics High 29610478
2018 Zbtb7a functions as a factor required for inducible changes in chromatin accessibility driven by transcription factors including NF-κB p65; Zbtb7a binds to a significant fraction of genomic promoters and enhancers, independently of client TF binding, and enables TF-dependent control of accessibility and normal gene expression. ATAC-seq, ChIP-seq, CRISPR/siRNA knockdown, p65 reporter assays PLoS biology High 29813070
2018 HP1γ/CBX3 directly represses expression of ZBTB7A in lung adenocarcinoma; knockdown of ZBTB7A significantly restores defects in proliferation, colony formation, and migration in HP1γ-depleted cells. ZBTB7A in turn downregulates expression of tumor-promoting factor AXL. ChIP, knockdown rescue experiments, in vivo K-RasG12D mouse model Cancer research Medium 29764865
2019 ZBTB7A is recruited to E2F-Rb binding sites by the androgen receptor (AR) and negatively regulates E2F1 transcriptional activity on DNA replication genes; AR recruitment of Rb strengthens the E2F-Rb repression complex, and ZBTB7A suppresses growth of castration-resistant prostate cancer in vitro and in vivo. ChIP-seq, RNA-seq, co-IP, in vitro and in vivo growth assays Cancer research High 31444154
2019 Under hypoxia, NF-κB (RelA/p65) represses ZBTB7A by binding NF-κB-binding elements in its promoter, downregulating FBI-1/ZBTB7A expression; loss of FBI-1 derepresses SLC16A3/MCT4, which is otherwise repressed by FBI-1 binding to FREs and HREs in the SLC16A3 promoter. Promoter reporter assays, oligonucleotide pulldown, ChIP, transfection experiments Biochimica et biophysica acta. Gene regulatory mechanisms Medium 31271899
2020 BMP4 activates Zbtb7a and Zbtb7b (Zbtb7a/b) expression during primed-to-naive stem cell transition; ZBTB7A in turn facilitates opening of naive pluripotent chromatin loci and activation of nearby genes, occupying both activated and silenced chromatin loci, consistent with dual roles in chromatin remodeling during pluripotent fate control. ATAC-seq, ChIP-seq, gene expression analysis, CRISPR-based functional assays Nature cell biology Medium 32393886
2020 Wild-type ZBTB7A prevents RUNX1-RUNX1T1-mediated clonal expansion of human CD34+ hematopoietic stem/progenitor cells; loss of ZBTB7A increases glycolysis and sensitizes leukemic blasts to metabolic inhibition with 2-deoxy-D-glucose. ZBTB7A expression causes cell cycle arrest that can be mimicked by glycolysis inhibition. Lentiviral transduction of CD34+ cells, proliferation assays, glycolysis measurement, cell cycle analysis Oncogene Medium 32115572
2021 X-ray crystal structures of the ZBTB7A DNA-binding domain (four zinc fingers ZF1-ZF4) in complex with the fetal globin promoter -200 element show that ZF1 and ZF2 recognize the 5' C:G quadruple while ZF4 contacts the 3' C:G quadruple; HPFH-associated mutations disrupt DNA binding, with most severe disruptions from mutations recognized by ZF1 and ZF2. X-ray crystallography, DNA binding assays with mutant probes Cell reports High 34592153
2009 LRF bypasses RAS(V12)-induced senescence in a CYCLIN E-dependent manner; LRF enhances E2F-dependent transcription and synergizes with RAS(V12) in activating E2F, independently of p19ARF, p21CIP, and p16INK4A. CYCLIN E induction is necessary for LRF-mediated bypass. cDNA expression screen, E2F reporter assays, cyclin E knockdown, senescence bypass assays Carcinogenesis Medium 19942610
2011 LRF forms an obligate dimer in B cells and regulates mature B cell lineage fate and humoral immune responses via distinctive mechanisms; LRF inactivation in transformed B cells attenuates their growth rate. B cell-specific conditional knockout mice, humoral immune response assays, B cell growth assays The Journal of clinical investigation Medium 21646720
2012 LRF negatively regulates osteoclast differentiation by repressing NFATc1 induction in the early phase of osteoclast development, while functioning as a coactivator of NFATc1 in the bone resorption phase; demonstrated using two conditional knockout mouse lines deleting LRF at early or late phases of osteoclast development. Stage-specific conditional knockout mice, NFATc1 expression analysis, osteoclast differentiation assays Proceedings of the National Academy of Sciences High 22308398
2014 ThPOK and LRF act redundantly to prevent transdifferentiation of mature CD4+ T cells into CD8+ T cells; post-thymic LRF deletion shows LRF maintains CD4+ T lineage integrity by restraining Runx3 expression and function. Post-thymic conditional gene deletion mouse model, T cell lineage analysis, Runx3 expression assays Nature immunology High 25129370
2022 LRF promotes integrin β7 (Itgb7) expression in thymic IEL precursors (IELps); LRF-deficient IELps fail to migrate to the intestine due to impaired α4β7 integrin expression. ChIP and gene-regulatory network analyses define Itgb7 as a direct LRF target gene. Conditional KO mice, scRNA-seq, ChIP, gut homing assays, gene-regulatory network analysis Nature immunology High 35354951
2008 FBI-1/ZBTB7A binds Sin3A and HDAC-1 to form a repressor complex via its N-terminal POZ domain; the POZ domain is required for Sin3A and HDAC-1 binding. FBI-1 represses E2F-4 promoter activity through a direct mechanism via a FBI-1 regulatory element, while repressing cyclin A through an indirect mechanism via inhibition of Sp1 binding. Co-IP, POZ domain mutagenesis, promoter reporter assays, direct binding assays Journal of molecular medicine Medium 18368381
2017 Thpok and LRF are redundantly required to maintain the size and functions of the postthymic Treg pool, supporting IL-2-mediated gene expression and Foxp3 function; Treg-specific disruption of Thpok and Lrf causes lethal inflammatory syndrome similar to Treg deficiency. Unlike in conventional T cells, Thpok and LRF functions in Tregs are not mediated by repression of Runx3. Treg-specific conditional knockout mice, inflammatory phenotype assessment, Foxp3 function analysis Journal of immunology Medium 28754678
2023 ZBTB7A directly binds to the HK2 and LDHA promoter regions and transcriptionally inhibits their expression, thereby regulating aerobic glycolysis in IDH1 wild-type glioblastoma cells; sdRNA U3-miR reduces ZBTB7A mRNA stability forming the U3/ZBTB7A/HK2/LDHA pathway. ChIP, promoter reporter assays, Seahorse glycolysis assay, RNA-binding studies CNS neuroscience & therapeutics Medium 37066523
2019 ZBTB7A binds to the promoter of LncRNA GAS5 and transcriptionally suppresses its expression, leading to decline in ER stress-induced cell apoptosis in osteosarcoma; miR-663a induced by ER stress directly targets the 3'UTR of ZBTB7A to downregulate it. ChIP, luciferase reporter assay, miRNA 3'UTR binding assay, apoptosis assays Cancer letters Medium 30753838
2018 ZBTB7A transcriptionally regulates ERα expression in ERα-positive breast cancer cell lines by binding to the ESR1 promoter, leading to increased ERα transcription; ERα in turn potentiates ZBTB7A expression via a post-translational mechanism, forming a positive feedback loop. ChIP, promoter reporter assays, ERE-luciferase assay, post-translational regulation analysis Journal of molecular cell biology Medium 30265334
2019 Inhibition of ZBTB7A upregulates E3 ligase TRIM25 leading to enhanced ERα ubiquitination and proteasomal degradation; ZBTB7A also transcriptionally increases ERα expression by indirectly binding to the region +146 to +461 bp downstream of the ESR1 transcription start site. Ubiquitination assays, ChIP, siRNA knockdown, proteasome inhibitor experiments Life sciences Medium 31715186
2023 ZBTB7A directly binds to the promoter of EPB41L5 and represses its expression, thereby inhibiting GBM progression and metastasis. RNA sequencing and ChIP confirm direct transcriptional repression of EPB41L5 by ZBTB7A. RNA-seq, ChIP, promoter reporter assays, in vitro and in vivo tumor assays Experimental & molecular medicine Medium 36596853

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science (New York, N.Y.) 300 26816381
2005 Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 276 15662416
2018 Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. Nature genetics 242 29610478
2011 Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 215 21483000
2012 The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood 182 23086750
2007 Regulation of B versus T lymphoid lineage fate decision by the proto-oncogene LRF. Science (New York, N.Y.) 180 17495164
1992 Interactions among LRF-1, JunB, c-Jun, and c-Fos define a regulatory program in the G1 phase of liver regeneration. Molecular and cellular biology 172 1406655
2013 Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion. Nature genetics 122 23727861
2009 The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. British journal of haematology 121 19291085
1999 Novel BTB/POZ domain zinc-finger protein, LRF, is a potential target of the LAZ-3/BCL-6 oncogene. Oncogene 119 9927193
2009 LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis. Developmental cell 100 19853566
2008 Proto-oncogene FBI-1 (Pokemon/ZBTB7A) represses transcription of the tumor suppressor Rb gene via binding competition with Sp1 and recruitment of co-repressors. The Journal of biological chemistry 84 18801742
2005 The transcription factor Pokemon: a new key player in cancer pathogenesis. Cancer research 83 16204018
2009 Proto-oncogene FBI-1 represses transcription of p21CIP1 by inhibition of transcription activation by p53 and Sp1. The Journal of biological chemistry 73 19244234
1997 Purification and characterization of FBI-1, a cellular factor that binds to the human immunodeficiency virus type 1 inducer of short transcripts. Molecular and cellular biology 70 9199312
2008 Proto-oncogene FBI-1 (Pokemon) and SREBP-1 synergistically activate transcription of fatty-acid synthase gene (FASN). The Journal of biological chemistry 68 18682402
2018 HP1γ Promotes Lung Adenocarcinoma by Downregulating the Transcription-Repressive Regulators NCOR2 and ZBTB7A. Cancer research 67 29764865
2008 The proto-oncogene LRF is under post-transcriptional control of MiR-20a: implications for senescence. PloS one 65 18596985
2014 A ThPOK-LRF transcriptional node maintains the integrity and effector potential of post-thymic CD4+ T cells. Nature immunology 64 25129370
2013 Role of LRF/Pokemon in lineage fate decisions. Blood 64 23396304
2021 Capsaicin Inhibits Proliferation and Induces Apoptosis in Breast Cancer by Down-Regulating FBI-1-Mediated NF-κB Pathway. Drug design, development and therapy 62 33469265
2007 Gene amplification is a relatively frequent event leading to ZBTB7A (Pokemon) overexpression in non-small cell lung cancer. The Journal of pathology 59 17907153
2017 LncRNA CCAT2 promotes tumorigenesis by over-expressed Pokemon in non-small cell lung cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 55 28088736
2015 C/EBPα-induced miR-100 expression suppresses tumor metastasis and growth by targeting ZBTB7A in gastric cancer. Cancer letters 55 26404754
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2010 MicroRNA (miRNA)-mediated interaction between leukemia/lymphoma-related factor (LRF) and alternative splicing factor/splicing factor 2 (ASF/SF2) affects mouse embryonic fibroblast senescence and apoptosis. The Journal of biological chemistry 53 20923760
2016 ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation. Nature communications 51 27252013
2020 BMP4 resets mouse epiblast stem cells to naive pluripotency through ZBTB7A/B-mediated chromatin remodelling. Nature cell biology 49 32393886
2011 Pro-oncogene Pokemon promotes breast cancer progression by upregulating survivin expression. Breast cancer research : BCR 49 21392388
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2003 Role of the POZ zinc finger transcription factor FBI-1 in human and murine adipogenesis. The Journal of biological chemistry 49 14701838
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2000 Repression of TNF-alpha-induced E-selectin expression by PPAR activators: involvement of transcriptional repressor LRF-1/ATF3. Biochemical and biophysical research communications 48 10964678
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2020 Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial. Leukemia 44 32015491
2019 ZBTB7A, a miR-663a target gene, protects osteosarcoma from endoplasmic reticulum stress-induced apoptosis by suppressing LncRNA GAS5 expression. Cancer letters 43 30753838
2012 LRF-mediated Dll4 repression in erythroblasts is necessary for hematopoietic stem cell maintenance. Blood 43 23134786
2013 The proto-oncoprotein FBI-1 interacts with MBD3 to recruit the Mi-2/NuRD-HDAC complex and BCoR and to silence p21WAF/CDKN1A by DNA methylation. Nucleic acids research 41 23658227
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2010 Overexpression of proto-oncogene FBI-1 activates membrane type 1-matrix metalloproteinase in association with adverse outcome in ovarian cancers. Molecular cancer 39 21176152
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2019 Hypoxia-induced RelA/p65 derepresses SLC16A3 (MCT4) by downregulating ZBTB7A. Biochimica et biophysica acta. Gene regulatory mechanisms 36 31271899
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2008 Overexpression of Pokemon in non-small cell lung cancer and foreshowing tumor biological behavior as well as clinical results. Lung cancer (Amsterdam, Netherlands) 36 18550205
2020 FBI-1 enhanced the resistance of triple-negative breast cancer cells to chemotherapeutic agents via the miR-30c/PXR axis. Cell death & disease 35 33051436
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2014 Pokemon (FBI-1) interacts with Smad4 to repress TGF-β-induced transcriptional responses. Biochimica et biophysica acta 34 25514493
2017 MicroRNA-520e suppresses non-small-cell lung cancer cell growth by targeting Zbtb7a-mediated Wnt signaling pathway. Biochemical and biophysical research communications 33 28242196
2008 Transcription factor FBI-1 acts as a dual regulator in adipogenesis by coordinated regulation of cyclin-A and E2F-4. Journal of molecular medicine (Berlin, Germany) 33 18368381
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2012 Functional analysis of the ATM-p53-p21 pathway in the LRF CLL4 trial: blockade at the level of p21 is associated with short response duration. Clinical cancer research : an official journal of the American Association for Cancer Research 28 22675167
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2009 Curcumin decreases the expression of Pokemon by suppressing the binding activity of the Sp1 protein in human lung cancer cells. Molecular biology reports 26 19444642
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2012 Stage-specific functions of leukemia/lymphoma-related factor (LRF) in the transcriptional control of osteoclast development. Proceedings of the National Academy of Sciences of the United States of America 25 22308398
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2018 Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study. Annals of hematology 24 30251205
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2020 The miR-372-ZBTB7A Oncogenic Axis Suppresses TRAIL-R2 Associated Drug Sensitivity in Oral Carcinoma. Frontiers in oncology 22 32083004
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2012 The oncogene LRF is a survival factor in chondrosarcoma and contributes to tumor malignancy and drug resistance. Carcinogenesis 17 22847180
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1985 The effects of thymus-derived peptides on hypothalamic LRF and pituitary gonadotropin content in prepubertal congenitally athymic nude mice and their normal heterozygous littermates. Journal of reproductive immunology 16 3928889
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2009 Eukaryotic translation initiator protein 1A isoform, CCS-3, enhances the transcriptional repression of p21CIP1 by proto-oncogene FBI-1 (Pokemon/ZBTB7A). Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 15 19471103
2023 ZBTB7A suppresses glioblastoma tumorigenesis through the transcriptional repression of EPB41L5. Experimental & molecular medicine 14 36596853
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2022 The transcription factor LRF promotes integrin β7 expression by and gut homing of CD8αα+ intraepithelial lymphocyte precursors. Nature immunology 13 35354951
2020 Obesity-Induced Upregulation of ZBTB7A Promotes Lipid Accumulation through SREBP1. BioMed research international 13 31998789
2016 Characterization of nuclear foci-targeting of Luman/CREB3 recruitment factor (LRF/CREBRF) and its potential role in inhibition of herpes simplex virus-1 replication. European journal of cell biology 13 28029379
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