Affinage

ZBTB16

Zinc finger and BTB domain-containing protein 16 · UniProt Q05516

Length
673 aa
Mass
74.3 kDa
Annotated
2026-04-28
100 papers in source corpus 48 papers cited in narrative 47 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZBTB16 (PLZF) is a BTB/POZ-zinc finger transcription factor that functions as a master regulator of stem cell self-renewal, innate immune cell differentiation, limb patterning, and inflammatory gene control, acting primarily as a transcriptional repressor but also as a context-dependent activator. Its BTB domain forms an obligate homodimer whose charged pocket recruits N-CoR/SMRT and mSin3A/HDAC1 co-repressor complexes to directly silence target promoters including c-myc, Kit, CRABPI, and early inflammatory response genes, while it activates CCR6 and REDD1 in specific immune and germ cell contexts (PMID:9627120, PMID:11865059, PMID:14645547, PMID:17664282, PMID:25605927, PMID:25833398). ZBTB16 activity is post-translationally tuned by SUMO-1 conjugation at K242 (enhancing DNA binding and repression), competitive ubiquitination at the same residue (promoting degradation under oxidative stress), HAT1-mediated acetylation (assembling an NF-κB-repressive HDAC3 complex), and cereblon-dependent degradation induced by thalidomide/IMiD compounds, which underlies thalidomide teratogenicity (PMID:14527952, PMID:18348865, PMID:25865065, PMID:33470442). Beyond transcription, ZBTB16 serves as the substrate-recognition subunit of a Cullin3-Roc1 E3 ubiquitin ligase targeting Atg14L for proteasomal degradation to regulate autophagy, and promotes ASC SUMOylation to control inflammasome assembly (PMID:25821988, PMID:38123560).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Establishing that PLZF represses transcription by directly recruiting histone deacetylase machinery resolved how this BTB-ZF protein silences target genes and explained the retinoic acid resistance of t(11;17) APL.

    Evidence Co-IP, in vitro binding, TSA inhibitor experiments, and reporter assays in cell lines; transgenic APL mouse models with SMRT interaction assays

    PMID:9462740 PMID:9627120 PMID:9765306

    Open questions at the time
    • Identity of direct genomic targets was not yet established
    • Whether PLZF can activate transcription was unknown
    • The contribution of individual co-repressor complexes (N-CoR vs. mSin3A) to specific biological processes remained unclear
  2. 1998 High

    The crystal structure of the BTB domain revealed obligate homodimerization and a surface-exposed groove at the dimer interface, providing the structural basis for co-repressor recruitment.

    Evidence X-ray crystallography at 1.9 Å resolution

    PMID:9770450

    Open questions at the time
    • No co-crystal with a co-repressor peptide was obtained
    • How zinc finger domains contribute to target specificity was structurally undefined
  3. 2000 High

    Loss-of-function in mice revealed PLZF as a patterning factor controlling limb and axial skeleton development through Hox gene and BMP regulation, establishing its first in vivo developmental role.

    Evidence Zfp145−/− knockout mouse with in situ hybridization and gene expression analysis

    PMID:10835630

    Open questions at the time
    • Direct DNA binding sites in Hox loci were not mapped
    • Relationship to other limb patterning transcription factors was unclear
  4. 2002 High

    Structure-function mutagenesis of the BTB charged pocket demonstrated that specific residues are required for co-repressor binding without disrupting dimerization, separating the structural and functional requirements of the BTB domain.

    Evidence Reconstituted binding assays with purified proteins and systematic point mutants, transcriptional reporter assays

    PMID:11865059

    Open questions at the time
    • Whether the charged pocket is the sole co-repressor interface was not excluded
    • No atomic-resolution co-complex structure was determined
  5. 2003 High

    Identification of c-myc, cyclin A2, and CRABPI as direct transcriptional targets, together with the discovery that SUMO-1 modification at K242 enhances DNA binding and repression, linked PLZF to cell cycle control and defined its first activating post-translational modification.

    Evidence ChIP, EMSA, reporter assays with mutated binding sites, site-directed mutagenesis of K242, cell cycle analysis

    PMID:14527952 PMID:14645547 PMID:18000064

    Open questions at the time
    • The SUMO E3 ligase responsible was not identified
    • Whether SUMO modification affects co-repressor recruitment was untested
    • Genome-wide target repertoire was unknown
  6. 2004 High

    Demonstration that Plzf is essential for spermatogonial stem cell self-renewal established the gene's role as a stem cell maintenance factor, with progressive germ cell depletion upon loss.

    Evidence Zfp145−/− knockout mice, spermatogonial transplantation assays, microarray of isolated spermatogonia

    PMID:15156142 PMID:15156143

    Open questions at the time
    • Direct transcriptional targets mediating self-renewal were not identified
    • Whether PLZF acts cell-autonomously in SSCs was not formally shown
  7. 2005 High

    Genetic epistasis with Gli3 showed cooperative control of proximal limb patterning, positioning PLZF within a broader signaling network for appendicular skeletal development.

    Evidence Gli3−/−;Plzf−/− double-mutant mice with cartilage condensation and cell death analysis

    PMID:16015334

    Open questions at the time
    • Whether PLZF and Gli3 physically interact or converge on shared targets was unknown
    • The downstream effectors in proximal mesenchyme were not defined
  8. 2007 High

    Direct binding and repression of Kit by PLZF in spermatogonia, validated by binding-site mutation and knockout, provided a molecular mechanism for how PLZF maintains the undifferentiated state of germ cells.

    Evidence ChIP, EMSA, reporter assay with 3-bp binding-site mutation, Plzf−/− mouse model

    PMID:17664282

    Open questions at the time
    • Whether Kit derepression alone is sufficient for differentiation was not tested
    • Other direct targets maintaining SSC identity remained uncharacterized
  9. 2008 High

    Discovery that K242 undergoes competitive SUMO-ubiquitin switching under oxidative stress, and that PLZF regulates miR-146a/CXCR4 in megakaryopoiesis, extended the regulatory logic to PTM-dependent protein stability and microRNA-mediated gene circuits.

    Evidence Site-directed mutagenesis and stability assays for SUMO/Ub switching; reporter assays, KD/OE with rescue for miR-146a pathway

    PMID:18348865 PMID:18568019

    Open questions at the time
    • The ubiquitin E3 ligase targeting K242 was not identified
    • Whether SUMO/Ub switching operates in vivo under physiological stress was unconfirmed
  10. 2009 High

    ERK-dependent nuclear export of PLZF in myeloid progenitors and interaction of PLZF-RARA with Polycomb (PRC1/Bmi-1) revealed signal-dependent inactivation and epigenetic co-opting mechanisms central to normal differentiation and leukemogenesis.

    Evidence Subcellular fractionation, ID2 knockdown rescue, Co-IP of PLZF-RARA with Bmi-1, ChIP at RA response elements, Bmi-1 KO

    PMID:19451220 PMID:19723763

    Open questions at the time
    • The kinase(s) directly phosphorylating PLZF for export were not mapped
    • Whether wild-type PLZF also engages PRC1 was not determined
  11. 2012 High

    Physical and functional antagonism between PLZF and SALL4 on shared chromatin targets in spermatogonia, and identification of USP37 as a deubiquitinase stabilizing PLZF-RARA, clarified how PLZF activity is modulated by protein partners and turnover.

    Evidence Reciprocal Co-IP, ChIP in Sall4/Plzf mutants; RNAi screen, ubiquitination and half-life assays for USP37

    PMID:22385656 PMID:23208507

    Open questions at the time
    • Whether SALL4 antagonism operates outside germ cells was unknown
    • USP37 relevance to wild-type PLZF (not just fusion) was not shown
  12. 2013 High

    PLZF was shown to repress L1 retrotransposons by inducing DNA methylation and to cooperate with Hox5 proteins to restrict Shh expression, broadening its role to genome defense and morphogen regulation.

    Evidence ChIP, bisulfite sequencing, L1 retrotransposition assay, compound Hox5/Plzf mutant mice

    PMID:23727884 PMID:24218595

    Open questions at the time
    • The DNA methyltransferase recruited by PLZF was not identified
    • Whether PLZF-dependent L1 silencing operates in somatic tissues was untested
  13. 2015 High

    Three convergent discoveries — PLZF as a CRL3 E3 ligase adaptor ubiquitinating Atg14L, HAT1-mediated acetylation assembling an NF-κB repressor complex, and genome-wide establishment of repressive chromatin at inflammatory genes — revealed non-transcriptional and anti-inflammatory effector functions.

    Evidence Co-IP and ubiquitination assays for CRL3-Atg14L; acetyltransferase assays, mutagenesis, Co-IP for HAT1-PLZF-HDAC3-p50; ChIP-seq and Plzf-KO inflammatory phenotyping

    PMID:25605927 PMID:25821988 PMID:25865065

    Open questions at the time
    • Whether CRL3-PLZF has additional ubiquitination substrates beyond Atg14L was unknown
    • The acetylation sites on PLZF were not fully mapped
    • Whether anti-inflammatory and E3 ligase functions operate in the same cell types was untested
  14. 2016 High

    Genome-wide ChIP-seq in spermatogonia and NKT cells mapped thousands of PLZF binding sites, showing preferential promoter occupancy, co-regulation with SALL4, and direct activation of T-helper programs including Bach2 suppression, providing a comprehensive target landscape.

    Evidence ChIP-seq, RNA-seq, microarray, siRNA KD in spermatogonia; biotinylation ChIP-seq in PLZF-transgenic thymocytes

    PMID:27068105 PMID:27325774

    Open questions at the time
    • A consensus DNA-binding motif for PLZF zinc fingers was not structurally resolved
    • Functional validation of most ChIP-seq targets was lacking
  15. 2020 High

    Identification of PLZF/ZBTB16 as a cereblon neosubstrate degraded by thalidomide and IMiD compounds, dependent on the first and third zinc fingers, established the molecular basis of thalidomide-induced limb teratogenicity.

    Evidence Protein array screen, cell-free ubiquitination, ZF domain mutagenesis, chicken embryo rescue; targeted degradation assays with CC-3060/CC-647

    PMID:33206504 PMID:33470442

    Open questions at the time
    • Whether PLZF degradation alone is sufficient for all teratogenic effects was not fully resolved
    • Structural basis of CRBN-ZF interaction was not determined at atomic resolution
  16. 2023 High

    ZBTB16 was found to promote ASC SUMOylation, controlling inflammasome assembly; ablation of ZBTB16 ameliorated inflammasome-driven pathology in Muckle-Wells syndrome, linking PLZF to innate immune inflammasome regulation.

    Evidence SUMOylation assays, Co-IP, ZBTB16 KO in Muckle-Wells mouse model

    PMID:38123560

    Open questions at the time
    • Whether PLZF directly acts as a SUMO E3 ligase or recruits one was not determined
    • The generalizability to other inflammasome-driven diseases was untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of PLZF zinc finger-DNA recognition, the full catalog of CRL3-PLZF ubiquitination substrates, and the mechanism by which PLZF switches between repressor and activator modes remain undefined.
  • No co-crystal structure of zinc fingers with a DNA target exists
  • Systematic identification of CRL3-PLZF substrates has not been performed
  • How context determines repression versus activation is mechanistically unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 8 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 7 GO:0005694 chromosome 3
Pathway
R-HSA-74160 Gene expression (Transcription) 10 R-HSA-1266738 Developmental Biology 5 R-HSA-168256 Immune System 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-4839726 Chromatin organization 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-9612973 Autophagy 1
Partners
BCL6CRBNCUL3HDAC1NCOR1NCOR2SALL4SIN3A
Complex memberships
CRL3 (Cullin3-Roc1) E3 ubiquitin ligaseN-CoR/SMRT co-repressor complexmSin3A/HDAC1 co-repressor complex

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PLZF BTB/POZ domain directly interacts with the mSin3A co-repressor (via PAH1 domain) and HDAC1 in vitro and in vivo, recruiting histone deacetylase activity to mediate transcriptional repression; trichostatin A (TSA) inhibition of HDACs significantly reduces PLZF repression. Co-immunoprecipitation, in vitro binding assays, TSA inhibitor experiments, reporter gene assays Oncogene High 9627120 9765306
1998 The PLZF BTB domain forms an obligate homodimer with an extensive hydrophobic interface, revealed at 1.9 Å resolution; a conserved surface-exposed groove at the dimer interface represents the site of interaction with nuclear co-repressors. X-ray crystallography at 1.9 Å resolution Proceedings of the National Academy of Sciences of the United States of America High 9770450
1998 PLZF-RARα and PML-RARα both interact with the SMRT co-repressor; however, PLZF-RARα forms RA-insensitive co-repressor complexes via its PLZF moiety, explaining RA resistance in t(11;17) APL. TSA combined with RA can overcome this repression. Transgenic mouse models, co-repressor interaction assays, TSA treatment experiments Nature genetics High 9462740
2002 Structure-function analysis demonstrated that the charged pocket of the PLZF BTB domain (formed at the dimer interface) is required for transcriptional repression and for direct interaction with N-CoR, SMRT, and HDACs; mutations neutralizing key charged pocket residues abolish co-repressor binding without disrupting dimerization. Structure-function mutagenesis, co-repressor binding assays with purified proteins, transcriptional reporter assays Molecular and cellular biology High 11865059
1998 PLZF interacts with multiple components of the SMRT co-repressor complex including mSin3A and HDAC1; these interactions are non-equivalent between PLZF and BCL-6; the oncogenic PLZF-RARα chimera lacks several co-repressor interaction sites present in native PLZF. Co-immunoprecipitation, GST pull-down The Journal of biological chemistry High 9765306
2003 PLZF directly represses c-myc transcription by binding to the c-myc promoter in vitro and in vivo, reducing RNA polymerase occupancy; c-myc repression mediates PLZF-induced cell cycle arrest, and ectopic c-myc expression reverses this arrest. Inducible PLZF cell line, microarray, ChIP, reporter assay with mutated binding site, EMSA Molecular and cellular biology High 14645547
2003 PLZF is modified by SUMO-1 conjugation at lysine 242 in the RD2 domain; this sumoylation is required for full transcriptional repression activity, increases DNA binding activity, and is necessary for PLZF-mediated cell cycle regulation and repression of cyclin A2. Site-directed mutagenesis, EMSA, luciferase reporter assay, cell cycle analysis The Journal of biological chemistry High 14527952
2004 PLZF (Zfp145/Plzf) is required in spermatogonial stem cells for self-renewal; loss of Plzf leads to progressive depletion of spermatogonial stem cells, increased apoptosis, and loss of tubule structure without overt differentiation defects. Knockout mouse (Zfp145-/-), spermatogonial transplantation, microarray analysis of isolated spermatogonia Nature genetics High 15156142 15156143
2007 PLZF directly represses Kit transcription by binding a discrete sequence in the kit promoter both in vivo (ChIP) and in vitro; a 3-bp mutation in the PLZF binding site abolishes repression; Kit expression is significantly increased in Plzf-/- undifferentiated spermatogonia. ChIP, EMSA, reporter assay with mutated binding site, Plzf-/- mouse model Molecular and cellular biology High 17664282
2000 Plzf is required for limb and axial skeletal patterning; Plzf inactivation causes homeotic transformations and alters expression of AbdB Hox genes and BMPs in the developing limb bud, acting as a growth-inhibitory and pro-apoptotic factor independently of known patterning genes. Zfp145-/- knockout mouse, in situ hybridization, gene expression analysis Nature genetics High 10835630
2009 PLZF/RARA directly interacts with the Polycomb group protein Bmi-1 and forms a stable component of the PRC1 complex, resulting in RA-insensitive ectopic recruitment of PRC1 to RA response elements; Bmi-1 is essential for PLZF/RARA cellular transformation. Co-immunoprecipitation, ChIP, Bmi-1 knockdown/KO experiments Genes & development High 19451220
2008 PLZF controls a regulatory pathway in megakaryopoiesis: PLZF binds and inhibits the miR-146a promoter, and miR-146a in turn targets CXCR4 mRNA to impede its translation; PLZF suppression of miR-146a thus activates CXCR4 translation to regulate megakaryocytic proliferation and differentiation. Reporter assays for miR-146a promoter, PLZF knockdown/overexpression, rescue experiments, in vitro megakaryopoiesis cultures Nature cell biology High 18568019
2012 During spermatogonial progenitor cell differentiation, Sall4 physically interacts with Plzf, sequesters Plzf to non-cognate chromatin domains to induce Kit expression; Plzf in turn displaces Sall4 from cognate chromatin to induce Sall1 expression, defining a functional antagonism between these factors. Co-immunoprecipitation, ChIP, gene expression analysis in Sall4/Plzf mutant models Cell stem cell High 22385656
2015 ZBTB16 functions as the substrate-recognition subunit of a ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex that ubiquitinates Atg14L to promote its proteasomal degradation; GPCR ligand activation regulates Atg14L levels and autophagy through this ZBTB16-dependent mechanism. Co-immunoprecipitation, ubiquitination assays, proteasomal degradation experiments, mouse model of Huntington's disease eLife High 25821988
2015 Let-7 miRNAs directly target Zbtb16 mRNA to post-transcriptionally downregulate PLZF expression during NKT cell development; IL-15, vitamin D, and retinoic acid signal upregulation of let-7 miRNAs, which direct terminal differentiation into IFN-γ-producing NKT1 cells. miRNA target validation, let-7 overexpression/knockdown, NKT cell developmental analysis in transgenic mice Nature immunology High 25848867
2015 TLR/TNF-α signaling triggers CaMK2 to activate HAT1, which then acetylates PLZF; acetylation of PLZF promotes assembly of a repressor complex incorporating HDAC3 and NF-κB p50 subunit to limit NF-κB transcriptional responses. Kinase activation assays, acetyltransferase assays, Co-IP of repressor complex, site-directed mutagenesis of acetylation sites, inflammatory cytokine readouts Nature communications High 25865065
2015 PLZF establishes basal repressive chromatin states at early response inflammatory genes by stabilizing a co-repressor complex with histone deacetylase activity; PLZF-deficient animals show exaggerated inflammatory cytokine responses. Genome-wide histone modification analysis (ChIP-seq), PLZF-KO mouse, temporal quantitation of inflammatory gene transcripts Proceedings of the National Academy of Sciences of the United States of America High 25605927
2003 PLZF directly represses CRABPI through propagation of chromatin condensation from a remote intronic binding element to silence the promoter; the reciprocal RARα-PLZF product binds this remote site, recruits p300, induces promoter hypomethylation and CRABPI gene upregulation. ChIP, reporter assays, chromatin analysis, cell line differentiation experiments Proceedings of the National Academy of Sciences of the United States of America High 18000064
2009 ERK1/2 activation by myeloid cytokines (stress response) causes nuclear export and inactivation of PLZF in human cord blood myeloid progenitors; PLZF represses transcription factors GFI-1, C/EBPα, and LEF-1, and induces negative regulators DUSP6 and ID2; loss of ID2 is a functional target that relieves PLZF-mediated repression of differentiation. PLZF promoter binding site analysis, ID2 knockdown rescue experiments, ERK activation assays, fractionation for nuclear export Genes & development High 19723763
2012 PLZF controls expression of a defined set of immune genes in NKT cells including c-Maf (which shapes cytokine profile) and Id2; ectopic c-Maf expression complemented the IL-4/IL-10 production defect in PLZF-deficient NKT cells. PLZF-KO mouse analysis, gene expression profiling, ectopic c-Maf expression rescue experiments Frontiers in immunology Medium 23267359
2016 ChIP-seq in mouse THY1+ spermatogonia identified PLZF preferentially binding gene promoters (4176 bound genes) while SALL4 preferentially bound introns; PLZF and SALL4 share 1295 target genes but motif analysis showed they occupy shared sites largely non-autonomously via PLZF motifs; KD of either factor suppresses mRNA levels of unique and shared targets. ChIP-seq, motif analysis, siRNA knockdown, RNA-seq Development (Cambridge, England) High 27068105
2016 ChIP-seq and microarray of NKT cells and PLZF-transgenic thymocytes revealed that PLZF: (1) directly binds and regulates cytokine and homing receptor genes; (2) activates T-helper-specific transcription factor genes; (3) binds and suppresses Bach2, a repressor of effector differentiation. Biotinylation-based ChIP-seq, microarray, PLZF-transgenic thymocytes Proceedings of the National Academy of Sciences of the United States of America High 27325774
2003 PLZF physically interacts with the RAR ligand-binding domain in a ligand-independent manner via its N-terminal zinc finger domain; this interaction inhibits RXR-RAR heterodimerization both in vitro and in intact cells, leading to decreased RAR transcriptional activity. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, reporter assays, heterodimerization assay Nuclear receptor High 14521715
2008 PLZF is SUMOylated at K242; the same residue can alternatively be ubiquitinated; oxidative stress (ROS from serum deprivation) inactivates SUMO-conjugating enzymes Uba2/Ubc9, shifting modification from SUMO to ubiquitin, destabilizing PLZF and inducing apoptosis via reduced BID repression. Site-directed mutagenesis, immunoprecipitation, stability assays, ROS measurement Biochemical and biophysical research communications Medium 18348865
2012 The deubiquitinase USP37 interacts with PLZF/RARA through the PLZF moiety and stabilizes PLZF/RARA by reducing its poly-ubiquitination; USP37 knockdown decreases PLZF/RARA half-life, alleviates target gene suppression, and reduces cell transformation potential. RNAi screen, Co-IP, domain mapping, protein half-life assays, ubiquitination assays, primary hematopoietic progenitor transduction Oncogene High 23208507
2021 PLZF/ZBTB16 is a neosubstrate of the CRL4CRBN ubiquitin ligase; thalidomide and 5-hydroxythalidomide promote CRBN-dependent degradation of PLZF in a manner dependent on the first and third zinc finger domains; PLZF degradation underlies thalidomide-induced limb teratogenicity. Human transcription factor protein array, cell-free protein synthesis system, ubiquitination assays, chicken embryo knockdown/overexpression, xenograft assays The EMBO journal High 33470442
2020 Cereblon modulators CC-3060 and CC-647 target ZBTB16 for proteasomal degradation through distinct structural degrons on different zinc finger domains; the same degrons are present in the ZBTB16-RARα and RARα-ZBTB16 fusion oncoproteins, which can also be degraded by these compounds. Targeted protein degradation assays, domain mapping, proteasome inhibitor experiments, structural degron identification ACS chemical biology High 33206504
2013 PLZF represses L1 retrotransposons by inducing DNA methylation at full-length L1 sequences, inhibiting L1 retrotransposition; PLZF also forms barrier-type boundaries by acting on truncated L1 sequences inserted in protein-coding genes; cell stress releases PLZF-mediated repression, leading to L1 activation. ChIP, bisulfite sequencing, L1 retrotransposition assay, PLZF KO/KD in germ and progenitor cells The EMBO journal High 23727884
2009 PLZF directly interacts with the (pro)renin receptor [(P)RR] and translocates to the nucleus upon renin stimulation, where it represses (P)RR itself and induces PI3K-p85α, leading to increased proliferation and decreased apoptosis. Protein-protein interaction assays, nuclear translocation studies, gene expression analysis Journal of molecular medicine (Berlin, Germany) Medium 18335187
2015 PLZF acts as a transcriptional activator of CCR6 in human Th17 cells by binding enhancer-like sites at -9/-10 and -13/-14 kb from the CCR6 upstream TSS; PLZF and RORC cross-regulate each other, and PLZF binds the RORC promoter. ChIP for modified histones, p300, and PLZF; siRNA knockdown; gene expression analysis in primary human T cells Journal of immunology (Baltimore, Md. : 1950) High 25833398
2017 A critical enhancer within the Zbtb16 locus, identified by CRISPR/Cas9 deletions, controls PLZF expression exclusively in innate lymphoid lineages; multiple Runx1-binding canonical motif sites within this enhancer are essential, with some controlling kinetics rather than overall levels of PLZF expression. Systematic CRISPR/Cas9-assisted enhancer deletions in vivo, ATAC-seq, ChIP-seq Nature communications High 29038474
2018 PLZF co-occupies chromatin with EZH2 at PLZF target genes independently of SUZ12 and H3K27me3 (PRC2), but associated with active H3K4me3 marks; removal of EZH2 increases PLZF binding and gene expression, revealing a non-canonical role of EZH2 in restricting PLZF positive transcriptional activity. ChIP-seq, EZH2 depletion, histone modification analysis Nucleic acids research Medium 29425303
2023 ZBTB16 promotes SUMOylation of ASC (apoptosis-associated speck-like protein containing a CARD) to control inflammasome assembly; ablation of ZBTB16 reduces hyperactive inflammasome pathogenesis in a mouse model of Muckle-Wells syndrome. SUMOylation assays, Co-IP, ZBTB16 knockout mouse, Muckle-Wells syndrome model Nature communications High 38123560
2000 LAZ3 (BCL-6) and PLZF directly interact via yeast two-hybrid, in vitro immunoprecipitation, and GST pull-down; heteromerization involves POZ/POZ contacts plus cross-contacts between zinc finger regions and POZ domains of each partner; the two proteins colocalize at nuclear dots. Yeast two-hybrid, in vitro immunoprecipitation, GST pull-down, immunofluorescence Oncogene High 11175338
2013 PLZF elevates FGFR3 expression and STAT3 pathway activity in neural progenitors, suppresses neurogenesis, and biases progenitors towards glial cell production; PLZF loss reduces FGFR3 levels and causes premature neuronal differentiation. PLZF overexpression/loss-of-function in spinal cord progenitors, FGFR3 expression assays, STAT3 pathway activation measurements PLoS biology High 24115909
2013 Hox5 proteins interact biochemically and genetically with PLZF to restrict Shh expression in the developing forelimb; loss of all three Hox5 genes (Hoxa5, Hoxb5, Hoxc5) combined with Plzf loss leads to anterior forelimb defects from Shh derepression. Genetic epistasis (compound mutant mice), biochemical interaction assays Proceedings of the National Academy of Sciences of the United States of America High 24218595
2005 Gli3 and Plzf cooperate genetically to establish proximal limb patterning; Gli3-/-;Plzf-/- double mutants show loss of all proximal hindlimb cartilage condensations with death of Bmpr1b-expressing proximal mesenchymal cells, while distal condensations are relatively unperturbed. Double-mutant mouse genetic epistasis, in situ hybridization, cell death analysis Nature High 16015334
2019 PLZF regulates proliferative activity of EOMES+ spermatogonial stem cells; in Plzf-null mice, EOMES+ SSCs have higher proliferation index, suggesting PLZF restrains their proliferative activity to prevent exhaustion. GDNF transgenic model, lineage tracing, busulfan challenge, RNAseq, scRNA-seq eLife Medium 31149899
2013 Znf179 directly interacts with Plzf (first two zinc fingers of Plzf are critical for interaction); Znf179 co-expression changes its own localization from cytoplasm to nucleus and increases Plzf protein abundance, though Plzf transcriptional repressor activity is unaffected in Gal4-dependent assays. Yeast two-hybrid, co-immunoprecipitation, domain mapping, subcellular localization analysis Journal of biomedical science Low 24359566
2009 Nuclear LYRIC/AEG-1 interacts with PLZF (via N- and C-termini of LYRIC and C-terminal to RD2 of PLZF); co-expression of LYRIC/AEG-1 reduces PLZF-mediated repression by decreasing PLZF binding to target promoters; both proteins colocalize to nuclear bodies containing HDACs. Yeast two-hybrid, co-immunoprecipitation in mammalian cells, ChIP, immunofluorescence colocalization Oncogene Medium 19648967
2019 REGγ proteasome activator loss increases p53 protein abundance in testis; p53 directly represses PLZF transcription, leading to decreased PLZF+ spermatogonia; partial p53 haplodeficiency rescues spermatogenesis defects in REGγ-null mice, establishing a REGγ-p53-PLZF pathway. REGγ knockout mouse, p53 haplodeficiency rescue (epistasis), p53-PLZF transcriptional repression in cell lines Stem cell reports High 31402338
2016 ZBTB16 acts downstream of Osterix (Osx) in osteoblastogenesis; ChIP assay showed Osx directly binds the ZBTB16 promoter at GC-rich Sp1 sequences; ZBTB16 silencing reduces alkaline phosphatase activity, osteocalcin/bone sialoprotein expression, and mineralized nodule formation; ZBTB16 overexpression induces osteogenic gene expression changes. ChIP assay, siRNA knockdown, transient transfection overexpression, ALP assay, Alizarin Red staining, microarray Journal of cellular biochemistry Medium 27335174
2024 Glucocorticoids increase basal progenitors co-expressing PAX6 and EOMES via ZBTB16 in human cerebral organoids and mice, leading to increased neuron production; a ZBTB16 enhancer variant that moderates glucocorticoid-induced ZBTB16 levels causally affects educational attainment and brain structure. Human cerebral organoids, ZBTB16 KO/OE, Mendelian randomization, prospective pregnancy cohort Neuron Medium 38442714
2020 KDM5B inhibits ZBTB16 expression by directly reducing H3K4me3 at the ZBTB16 promoter; loss of ZBTB16 then increases TOP2A expression to confer cisplatin resistance; USP7 stabilizes KDM5B by deubiquitination, thereby indirectly regulating the ZBTB16/TOP2A axis. ChIP-H3K4me3 at ZBTB16 promoter, siRNA knockdown/overexpression, in vitro and in vivo tumor assays Cell death and differentiation Medium 38287116
2013 PLZF directly binds the HOXB7 locus and regulates Hox gene expression in the developing limb; Plzf-/- limb buds show anterior expansion of Hoxd10-13 expression domains in the absence of ectopic Sonic hedgehog, and a 2,964-bp intronic deletion reducing Plzf expression recapitulates this (polydactyly). In situ hybridization, quantitative RT-PCR, linkage mapping, conserved noncoding element deletion analysis Developmental dynamics Medium 19191224
2023 Super enhancers recruit BRD4 to the ZBTB16 locus, which then binds RPAP2 to transport RNA Pol II into the nucleus; BRD4 and RPAP2 synergistically regulate Pol II CTD phosphorylation (BRD4 phosphorylates Ser2, RPAP2 dephosphorylates Ser5) to initiate ZBTB16 transcriptional elongation during MSC osteogenesis. ChIP-seq, ATAC-seq, BRD4 inhibition, bone-targeting ZBTB16 overexpression in Brd4fl/fl Prx1-cre mice, OP models Bone research Medium 37280207
2011 PLZF activates REDD1 transcription, which mediates PLZF-dependent downregulation of TORC1 and maintenance of pluripotency in spermatogonial progenitor cells; PLZF also represses smooth muscle α-actin transcription, reorganizing the cytoskeleton and conferring resistance to oncogenic transformation. Target gene identification, TORC1 activity assay, cytoskeletal analysis, oncogenic transformation assays Cell cycle (Georgetown, Tex.) Medium 21311223

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Essential role of Plzf in maintenance of spermatogonial stem cells. Nature genetics 761 15156143
2004 Plzf is required in adult male germ cells for stem cell self-renewal. Nature genetics 717 15156142
1998 Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL. Nature genetics 488 9462740
1998 Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein. Oncogene 258 9627120
1998 Crystal structure of the BTB domain from PLZF. Proceedings of the National Academy of Sciences of the United States of America 256 9770450
2000 Plzf regulates limb and axial skeletal patterning. Nature genetics 244 10835630
2010 T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells. Nature immunology 217 20601952
2008 A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis. Nature cell biology 192 18568019
2002 Critical residues within the BTB domain of PLZF and Bcl-6 modulate interaction with corepressors. Molecular and cellular biology 178 11865059
2000 Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARalpha and PLZF-RARalpha oncoproteins. Proceedings of the National Academy of Sciences of the United States of America 164 10954752
2007 Repression of kit expression by Plzf in germ cells. Molecular and cellular biology 159 17664282
2012 Functional antagonism between Sall4 and Plzf defines germline progenitors. Cell stem cell 143 22385656
1998 Components of the SMRT corepressor complex exhibit distinctive interactions with the POZ domain oncoproteins PLZF, PLZF-RARalpha, and BCL-6. The Journal of biological chemistry 140 9765306
2015 Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function. Nature immunology 121 25848867
1995 Leukemia translocation gene, PLZF, is expressed with a speckled nuclear pattern in early hematopoietic progenitors. Blood 117 8541544
2003 Growth suppression by acute promyelocytic leukemia-associated protein PLZF is mediated by repression of c-myc expression. Molecular and cellular biology 113 14645547
2009 The PRC1 Polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation. Genes & development 109 19451220
1997 Opposite effects of the acute promyelocytic leukemia PML-retinoic acid receptor alpha (RAR alpha) and PLZF-RAR alpha fusion proteins on retinoic acid signalling. Molecular and cellular biology 109 9234742
1995 Expression of the zinc-finger gene PLZF at rhombomere boundaries in the vertebrate hindbrain. Proceedings of the National Academy of Sciences of the United States of America 104 7892256
2012 Human iNKT and MAIT cells exhibit a PLZF-dependent proapoptotic propensity that is counterbalanced by XIAP. Blood 87 23223428
2015 G-protein-coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L. eLife 86 25821988
2009 PLZF is a regulator of homeostatic and cytokine-induced myeloid development. Genes & development 84 19723763
1999 Retinoic acid, but not arsenic trioxide, degrades the PLZF/RARalpha fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient. Oncogene 84 10023688
2005 Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. Nature 83 16015334
1999 Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARalpha and NPM-RARalpha. Proceedings of the National Academy of Sciences of the United States of America 83 10339585
2016 The regulatory repertoire of PLZF and SALL4 in undifferentiated spermatogonia. Development (Cambridge, England) 82 27068105
2016 Multiple layers of transcriptional regulation by PLZF in NKT-cell development. Proceedings of the National Academy of Sciences of the United States of America 82 27325774
2011 Development of PLZF-expressing innate T cells. Current opinion in immunology 78 21257299
2016 Concise Review: Balancing Stem Cell Self-Renewal and Differentiation with PLZF. Stem cells (Dayton, Ohio) 75 26676652
2006 Histone lysine trimethylation exhibits a distinct perinuclear distribution in Plzf-expressing spermatogonia. Developmental biology 75 16549060
2008 The transcriptional regulator PLZF induces the development of CD44 high memory phenotype T cells. Proceedings of the National Academy of Sciences of the United States of America 71 19004789
2015 The acetyltransferase HAT1 moderates the NF-κB response by regulating the transcription factor PLZF. Nature communications 68 25865065
2021 Thalidomide and its metabolite 5-hydroxythalidomide induce teratogenicity via the cereblon neosubstrate PLZF. The EMBO journal 67 33470442
2000 Colocalization and heteromerization between the two human oncogene POZ/zinc finger proteins, LAZ3 (BCL6) and PLZF. Oncogene 65 11175338
2019 CD161 contributes to prenatal immune suppression of IFNγ-producing PLZF+ T cells. The Journal of clinical investigation 64 31145102
2015 BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs. Proceedings of the National Academy of Sciences of the United States of America 60 25605927
2014 Polyclonal type II natural killer T cells require PLZF and SAP for their development and contribute to CpG-mediated antitumor response. Proceedings of the National Academy of Sciences of the United States of America 60 24550295
2009 Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression. Oncogene 60 19648967
2019 Identification of EOMES-expressing spermatogonial stem cells and their regulation by PLZF. eLife 59 31149899
2004 Role of PLZF in melanoma progression. Oncogene 57 15077196
2017 A shared Runx1-bound Zbtb16 enhancer directs innate and innate-like lymphoid lineage development. Nature communications 54 29038474
2007 RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America 54 18000064
2021 Zbtb16 regulates social cognitive behaviors and neocortical development. Translational psychiatry 46 33895774
2006 PLZF regulates Pbx1 transcription and Pbx1-HoxC8 complex leads to androgen-independent prostate cancer proliferation. The Prostate 45 16637071
2018 ZBTB16 Overexpression Enhances White Adipogenesis and Induces Brown-Like Adipocyte Formation of Bovine White Intramuscular Preadipocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 44 30121655
2012 PLZF Controls the Expression of a Limited Number of Genes Essential for NKT Cell Function. Frontiers in immunology 44 23267359
2003 Modification of promyelocytic leukemia zinc finger protein (PLZF) by SUMO-1 conjugation regulates its transcriptional repressor activity. The Journal of biological chemistry 44 14527952
1998 The acute promyelocytic leukaemia specific PML and PLZF proteins localize to adjacent and functionally distinct nuclear bodies. Oncogene 43 9591778
2013 Hox5 interacts with Plzf to restrict Shh expression in the developing forelimb. Proceedings of the National Academy of Sciences of the United States of America 41 24218595
2004 Identification and characterization of PLZF as a prostatic androgen-responsive gene. The Prostate 41 15065091
1996 PML, PLZF and NPM genes in the molecular pathogenesis of acute promyelocytic leukemia. Haematologica 41 8952164
2015 Synergistic Leukemia Eradication by Combined Treatment with Retinoic Acid and HIF Inhibition by EZN-2208 (PEG-SN38) in Preclinical Models of PML-RARα and PLZF-RARα-Driven Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 39 25931453
2003 Regulation of Hoxb2 by APL-associated PLZF protein. Oncogene 39 12802276
2018 PLZF inhibits proliferation and metastasis of gallbladder cancer by regulating IFIT2. Cell death & disease 38 29358655
2017 Downregulation of Plzf Gene Ameliorates Metabolic and Cardiac Traits in the Spontaneously Hypertensive Rat. Hypertension (Dallas, Tex. : 1979) 38 28396530
2012 The deubiquitinating enzyme USP37 regulates the oncogenic fusion protein PLZF/RARA stability. Oncogene 38 23208507
2024 Deubiquitinase USP7 stabilizes KDM5B and promotes tumor progression and cisplatin resistance in nasopharyngeal carcinoma through the ZBTB16/TOP2A axis. Cell death and differentiation 36 38287116
2015 PLZF regulates CCR6 and is critical for the acquisition and maintenance of the Th17 phenotype in human cells. Journal of immunology (Baltimore, Md. : 1950) 36 25833398
2017 ZBTB16 and metabolic syndrome: a network perspective. Physiological research 35 28948820
2013 PLZF regulates fibroblast growth factor responsiveness and maintenance of neural progenitors. PLoS biology 34 24115909
2010 PLZF/ZBTB16, a glucocorticoid response gene in acute lymphoblastic leukemia, interferes with glucocorticoid-induced apoptosis. The Journal of steroid biochemistry and molecular biology 34 20435142
2007 Identification of apoptosis-related PLZF target genes. Biochemical and biophysical research communications 34 17537403
2020 Long noncoding RNA PART1 restrains aggressive gastric cancer through the epigenetic silencing of PDGFB via the PLZF-mediated recruitment of EZH2. Oncogene 33 32901105
2020 Cereblon Modulators Target ZBTB16 and Its Oncogenic Fusion Partners for Degradation via Distinct Structural Degrons. ACS chemical biology 33 33206504
2017 Role of PLZF as a tumor suppressor in prostate cancer. Oncotarget 33 29050363
2016 ZBTB16 as a Downstream Target Gene of Osterix Regulates Osteoblastogenesis of Human Multipotent Mesenchymal Stromal Cells. Journal of cellular biochemistry 33 27335174
2018 Human endometrial stromal cell decidualization requires transcriptional reprogramming by PLZF. Biology of reproduction 32 29186366
2003 PLZF is a negative regulator of retinoic acid receptor transcriptional activity. Nuclear receptor 32 14521715
2019 Androgen promotes differentiation of PLZF+ spermatogonia pool via indirect regulatory pattern. Cell communication and signaling : CCS 31 31142324
2015 Loss of PLZF expression in prostate cancer by immunohistochemistry correlates with tumor aggressiveness and metastasis. PloS one 31 25807461
2013 The epigenetic regulator PLZF represses L1 retrotransposition in germ and progenitor cells. The EMBO journal 31 23727884
2008 Increased expression of the tumor suppressor PLZF is a continuous predictor of long-term survival in malignant melanoma patients. Cancer biotherapy & radiopharmaceuticals 30 18771349
2015 miR-544 Regulates Dairy Goat Male Germline Stem Cell Self-Renewal via Targeting PLZF. Journal of cellular biochemistry 29 25808723
2008 PLZF and the (pro)renin receptor. Journal of molecular medicine (Berlin, Germany) 28 18335187
2023 Inflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC. Nature communications 26 38123560
2018 Regulation of the positive transcriptional effect of PLZF through a non-canonical EZH2 activity. Nucleic acids research 26 29425303
2014 Dexamethasone-related osteogenic differentiation of dental follicle cells depends on ZBTB16 but not Runx2. Cell and tissue research 26 24816988
2013 Plzf as a candidate gene predisposing the spontaneously hypertensive rat to hypertension, left ventricular hypertrophy, and interstitial fibrosis. American journal of hypertension 26 23975223
2009 PLZF-mediated control on c-kit expression in CD34(+) cells and early erythropoiesis. Oncogene 25 19421145
2013 Analysis of the interaction between Zinc finger protein 179 (Znf179) and promyelocytic leukemia zinc finger (Plzf). Journal of biomedical science 24 24359566
2007 The PLZF gene of t (11;17)-associated APL. Current topics in microbiology and immunology 24 17217037
2024 Human cortical neurogenesis is altered via glucocorticoid-mediated regulation of ZBTB16 expression. Neuron 23 38442714
2020 PLZF-RARα, NPM1-RARα, and Other Acute Promyelocytic Leukemia Variants: The PETHEMA Registry Experience and Systematic Literature Review. Cancers 23 32455804
2016 ZBTB16: a novel sensitive and specific biomarker for yolk sac tumor. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 23 26916077
2011 Understanding PLZF: two transcriptional targets, REDD1 and smooth muscle α-actin, define new questions in growth control, senescence, self-renewal and tumor suppression. Cell cycle (Georgetown, Tex.) 23 21311223
2017 Tangshen formula attenuates diabetic renal injuries by upregulating autophagy via inhibition of PLZF expression. PloS one 22 28182710
2023 Super enhancers targeting ZBTB16 in osteogenesis protect against osteoporosis. Bone research 21 37280207
2011 Characterisation of genome-wide PLZF/RARA target genes. PloS one 21 21949697
2019 The REGγ-Proteasome Regulates Spermatogenesis Partially by P53-PLZF Signaling. Stem cell reports 20 31402338
2011 The promyelocytic leukemia zinc finger (PLZF) protein exerts neuroprotective effects in neuronal cells and is dysregulated in experimental stroke. Brain pathology (Zurich, Switzerland) 20 20731660
2009 Deletion of a conserved noncoding sequence in Plzf intron leads to Plzf down-regulation in limb bud and polydactyly in the rat. Developmental dynamics : an official publication of the American Association of Anatomists 20 19191224
2021 Optineurin deletion disrupts metabotropic glutamate receptor 5-mediated regulation of ERK1/2, GSK3β/ZBTB16, mTOR/ULK1 signaling in autophagy. Biochemical pharmacology 19 33513340
2019 Acute promyelocytic leukemia and variant fusion proteins: PLZF-RARα fusion protein at a glance. Seminars in oncology 19 31126665
2014 Innate PLZF+CD4+ αβ T cells develop and expand in the absence of Itk. Journal of immunology (Baltimore, Md. : 1950) 19 24928994
2013 8-CPT-cAMP/all-trans retinoic acid targets t(11;17) acute promyelocytic leukemia through enhanced cell differentiation and PLZF/RARα degradation. Proceedings of the National Academy of Sciences of the United States of America 19 23382200
2008 Redox-mediated modification of PLZF by SUMO-1 and ubiquitin. Biochemical and biophysical research communications 19 18348865
2001 Acute promyelocytic leukemia with a PLZF-RARalpha fusion protein. Seminars in hematology 19 11172538
2017 ZBTB16 gene variability influences obesity-related parameters and serum lipid levels in Czech adults. Physiological research 18 28948827
2014 Downregulation of PLZF in human hepatocellular carcinoma and its clinical significance. Oncology reports 18 25369784
2017 Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis. Molecular and cellular biology 17 28416638