Affinage

ZEB2

Zinc finger E-box-binding homeobox 2 · UniProt O60315

Length
1214 aa
Mass
136.4 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZEB2 is a multi-zinc finger transcription factor that functions as a master regulator of cell identity transitions across epithelial, neural, hematopoietic, immune, and vascular lineages, primarily by repressing lineage-inappropriate gene programs. ZEB2 represses E-cadherin, cyclin D1, ephrinB2, and other target genes by binding E-box and related promoter elements, recruiting the NuRD/HDAC1 corepressor complex to mediate transcriptional silencing, while also acting as a transcriptional activator of select targets (e.g., cadherin-11, ACSL4, ETS1) through cooperation with Sp1 or direct E-box engagement (PMID:11430829, PMID:17855508, PMID:18182442, PMID:36951067, PMID:24130169). ZEB2 operates within a double-negative feedback loop with the miR-200 family—each repressing the other's expression—and its protein levels are further controlled by the Zeb2-NAT antisense transcript that promotes its translation, by ubiquitin-proteasome-mediated degradation, and by upstream transcription factors including HIF-1α, NFIL3, C/EBPs, FoxQ1, and MEF2A (PMID:18829540, PMID:17585049, PMID:29311544, PMID:21727196, PMID:35732734). In the immune system, ZEB2 drives age-associated B cell and terminal effector CD8+ T cell differentiation, specifies cDC2 fate through an Nfil3-Zeb2-Id2 circuit, programs tumor-associated macrophage identity, and is required broadly for hematopoietic lineage output; in the nervous system it controls cortical interneuron migration (via Unc5b repression), axonal growth (via ninein), Schwann cell myelination, Bergmann glia specification, and astrogliosis (PMID:38271512, PMID:29449309, PMID:31406377, PMID:40215981, PMID:23312517, PMID:25741725, PMID:27294512, PMID:32610135).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    The central question of how ZEB2 drives epithelial-to-mesenchymal transition was answered by demonstrating that ZEB2 directly represses E-cadherin through binding to conserved E2-boxes in its promoter, establishing ZEB2 as a direct transcriptional repressor of cell adhesion.

    Evidence Promoter binding assays with E-box mutagenesis and conditional expression in MDCK cells

    PMID:11430829

    Open questions at the time
    • Whether ZEB2 requires cofactors for E-cadherin repression was not addressed
    • Genome-wide binding profile not yet determined
    • Post-translational regulation of ZEB2 unknown
  2. 2006 Medium

    ZEB2's transcriptional program was extended beyond E-cadherin repression to include activation of mesenchymal genes (vimentin) and matrix metalloproteinases, and its regulation was linked to the HIF-VHL oxygen-sensing axis, connecting ZEB2 to tumor hypoxia responses.

    Evidence RNAi and overexpression in breast cancer and renal carcinoma cells; VHL re-expression and HIF knockdown epistasis

    PMID:15026811 PMID:16568083 PMID:17060462

    Open questions at the time
    • Whether HIF directly binds the ZEB2 promoter was not resolved
    • Mechanism of vimentin activation (direct vs. indirect) undetermined
  3. 2008 High

    Three breakthroughs established ZEB2's regulatory architecture: (1) a double-negative feedback loop with miR-200 family was identified, creating a bistable EMT switch; (2) ZEB2 was shown to repress cyclin D1, coupling EMT to cell cycle arrest; and (3) ZEB2 was found to recruit the NuRD corepressor complex, with a Mowat-Wilson syndrome patient mutation disrupting this interaction.

    Evidence ChIP, promoter reporters, miRNA overexpression/inhibition; mass spectrometry of affinity-purified complexes; Xenopus neural induction assays with domain mutants

    PMID:17855508 PMID:18182442 PMID:18376396 PMID:18829540

    Open questions at the time
    • Structural basis of NuRD-ZEB2 interaction unresolved
    • Whether ZEB2 and ZEB1 have redundant roles in the miR-200 loop not fully dissected
    • Whether NuRD mediates all or only some ZEB2 repressive activities unknown
  4. 2010 Medium

    ZEB2's role was expanded beyond cancer EMT to pluripotency decisions: in human ESCs, ZEB2 limits Activin-Nodal/SMAD signaling to direct neuroectodermal versus mesendodermal specification.

    Evidence Loss- and gain-of-function in hESCs with epistasis to Activin-Nodal pathway components

    PMID:20074535

    Open questions at the time
    • Direct transcriptional targets in hESC context not identified by ChIP
    • Whether ZEB2 engages NuRD in this context untested
  5. 2011 Medium

    Post-translational control of ZEB2 protein stability was established: the F-box protein Ppa targets ZEB2 for ubiquitin-proteasome degradation, providing a mechanism for rapid EMT factor turnover.

    Evidence Protein stability assays, proteasome inhibitor treatment, domain mapping, Xenopus epistasis

    PMID:21727196

    Open questions at the time
    • Specific ubiquitin chain type and lysine residues not mapped
    • Whether Ppa is the sole E3 ligase for ZEB2 unknown
    • Regulation of Ppa itself not addressed
  6. 2013 Medium

    ZEB2 was shown to function as a transcriptional activator—not only a repressor—by cooperating with Sp1 to transactivate cadherin-11 and integrin α5, and by directly activating ETS1, revealing a dual-mode transcription factor.

    Evidence ChIP and promoter reporters for Sp1-dependent activation; ChIP on ETS1 promoter with inducible ZEB2 expression

    PMID:24130169 PMID:30790340

    Open questions at the time
    • Structural basis for context-dependent switching between repression and activation unknown
    • Whether Sp1 cooperation is genome-wide or restricted to specific loci untested
  7. 2013 High

    ZEB2's essential role in cortical interneuron migration was mechanistically resolved: Zeb2 represses the guidance receptor Unc5b, and genetic reduction of Unc5b rescues migration in Zeb2-null interneurons, establishing a repressor-of-repulsion mechanism.

    Evidence Conditional Zeb2 KO in interneurons, RNA-seq, focal Unc5b electroporation rescue

    PMID:23312517

    Open questions at the time
    • Whether additional guidance receptors are ZEB2 targets not fully explored
    • Mechanism of ZEB2 binding at Unc5b locus not shown by ChIP
  8. 2015 High

    ZEB2's control of axonal morphogenesis was traced to a specific effector: ninein, a microtubule-binding protein directly activated by ZEB2, mediates axonal growth and cortical branching.

    Evidence Conditional Zeb2 KO in postmitotic neurons, ChIP confirming ninein as direct target, ninein rescue experiments

    PMID:25741725

    Open questions at the time
    • Whether ninein is the sole mediator of ZEB2-dependent axonal phenotypes unknown
    • How ZEB2 activates rather than represses ninein transcription mechanistically unclear
  9. 2016 High

    ZEB2 was established as essential for multiple neural and hematopoietic lineages: Schwann cell myelination (repressing Sox2/Ednrb as an 'inhibitor of inhibitors'), broad hematopoietic differentiation (regulating JAK-STAT and ERK signaling, M-CSF receptor expression, and pDC development), and myeloid differentiation in AML (controlled by miR-200 methylation).

    Evidence Schwann cell-specific and bone marrow-inducible Zeb2 KO in mice; RNA-seq; genome-scale shRNA screens in AML

    PMID:27294512 PMID:27683414 PMID:27756750 PMID:27930303

    Open questions at the time
    • Direct ChIP targets in hematopoietic cells not systematically mapped
    • Whether ZEB2 roles in pDC and monocyte development share common target genes unknown
  10. 2018 Medium

    ZEB2's immune functions were extended to adaptive immunity and its translational regulation clarified: ZEB2 promotes terminal effector CD8+ T cell fate (opposing ZEB1-driven memory), interacts with the demethylase KDM1A/LSD1 in T-ALL, and the Zeb2-NAT antisense lncRNA controls ZEB2 protein translation, influencing somatic cell reprogramming.

    Evidence Conditional KO of Zeb1/Zeb2 in CD8+ T cells; co-IP of ZEB2-KDM1A; LNA knockdown of Zeb2-NAT with reprogramming and pluripotency assays

    PMID:28069602 PMID:29311544 PMID:29326173 PMID:29449309

    Open questions at the time
    • Whether KDM1A interaction is direct or bridged by NuRD not resolved
    • p53-miR-30a-ZEB2 axis identified concurrently but integration with miR-200 loop unclear
    • Zeb2-NAT mechanism of translational control (IRES retention vs. other) not fully dissected
  11. 2019 High

    A complete genetic circuit governing dendritic cell specification was delineated: NFIL3 represses Zeb2, and low Zeb2 permits Id2 upregulation to commit progenitors to the cDC1 lineage, positioning Zeb2 as the central node in DC fate decisions.

    Evidence Genetic epistasis in conditional KO mice, CUT&RUN and ChIP-seq for direct NFIL3 binding at Zeb2

    PMID:31406377

    Open questions at the time
    • How Zeb2 represses Id2 (direct binding vs. intermediate) not shown
    • Whether this circuit operates identically in human DC development untested
  12. 2022 High

    Enhancer-level regulatory logic of Zeb2 was resolved: NFIL3 and C/EBP factors bind a −165 kb Zeb2 enhancer with opposing effects, and triple CRISPR mutation of these sites ablates Zeb2 selectively in myeloid progenitors, causing complete loss of cDC2 specification; simultaneously, ZEB2 was shown to control smooth muscle cell phenotypic transitions during atherosclerosis through chromatin remodeling.

    Evidence CUT&RUN/ChIP-seq with in vivo CRISPR triple-site mutagenesis; scATAC-seq and scRNA-seq in SMC-specific Zeb2 KO atherosclerosis model

    PMID:34990206 PMID:35732734

    Open questions at the time
    • Whether additional distal enhancers regulate Zeb2 in other lineages unknown
    • How ZEB2 remodels chromatin at SMC loci—direct NuRD recruitment vs. other mechanisms—not resolved
  13. 2023 High

    ZEB2's effector mechanism was further specified in endothelial pathology: ZEB2 recruits the HDAC1-NuRD complex to repress CTH/CSE, reducing H2S and PDI S-sulfhydration to drive aortic aneurysm; separately, a ZEB2-ACSL4 positive feedback loop linking transcriptional activation to protein stabilization was identified in breast cancer metastasis.

    Evidence Co-IP/MS, ChIP at CTH promoter, endothelial HDAC1 KO mice; ChIP at ACSL4 promoter with ubiquitination assays and in vivo metastasis models

    PMID:36951067 PMID:38078907

    Open questions at the time
    • Whether ACSL4-mediated ZEB2 stabilization occurs in non-cancer contexts unknown
    • Specific HDAC1 deacetylation targets at the CTH locus not identified
  14. 2024 High

    ZEB2 was identified as a driver of age-associated B cell differentiation by directly repressing the MEF2B intronic enhancer, thereby blocking germinal center fate; ZEB2 haploinsufficiency in humans reduces ABC formation, and JAK-STAT signaling is required for ZEB2-driven ABC differentiation, linking ZEB2 to autoimmunity.

    Evidence ZEB2 haploinsufficient human subjects, B cell-specific Zeb2 KO mice, ChIP/binding at MEF2B enhancer, JAK inhibitor treatment in TLR7-driven lupus model

    PMID:38271512

    Open questions at the time
    • Full ZEB2 cistrome in B cells not yet mapped
    • Whether ZEB2-driven ABC program is identical across autoimmune diseases unknown
  15. 2025 Medium

    ZEB2 was established as the master transcription factor of tumor-associated macrophage identity, controlling chromatin accessibility, interferon response suppression, and immune evasion programs; genetic ablation of Zeb2 in TAMs reprograms them and mobilizes anti-tumor T cell responses.

    Evidence Integrative scRNA-seq with CRISPR screen, gene perturbation network analysis, conditional Zeb2 KO in TAMs with in vivo tumor models

    PMID:40215981

    Open questions at the time
    • Direct ZEB2 target genes in TAMs not validated by ChIP
    • Whether TAM reprogramming by ZEB2 deletion synergizes with checkpoint immunotherapy not tested
    • Single lab finding awaiting independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • A genome-wide, cell-type-resolved map of ZEB2 binding sites across its diverse lineage contexts is lacking, and the structural basis for ZEB2's context-dependent switching between transcriptional repression (NuRD/HDAC recruitment) and activation (Sp1 cooperation) remains unresolved.
  • No crystal or cryo-EM structure of ZEB2 or ZEB2-NuRD complex
  • Systematic CUT&RUN/ChIP-seq across immune, neural, and epithelial contexts not performed
  • How ZEB2 versus ZEB1 target specificity is achieved at the DNA-binding level is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 15 GO:0003677 DNA binding 12
Localization
GO:0005634 nucleus 10
Pathway
R-HSA-168256 Immune System 6 R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 4 R-HSA-4839726 Chromatin organization 3
Partners
ACSL4CHD3HDAC1KDM1ANFIL3SP1
Complex memberships
NuRD

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 ZEB2/SIP1 directly represses E-cadherin transcription by binding to both conserved E2-boxes of the minimal E-cadherin promoter, and conditional expression in E-cadherin-positive MDCK cells abrogates E-cadherin-mediated intercellular adhesion and induces invasion. Promoter binding assays, E-box mutagenesis, conditional expression in MDCK cells, invasion assays Molecular cell High 11430829
2008 ZEB2/SIP1 (together with ZEB1) represses the miR-200 family promoter by binding to conserved ZEB-type E-box elements, establishing a double-negative feedback loop: miR-200 family suppresses ZEB1/ZEB2, and ZEB1/ZEB2 suppress miR-200 family expression. Promoter deletion analysis, ChIP, reporter assays, enforced expression/inhibition of miRNAs Cancer research High 18376396 18829540
2008 ZEB2/SIP1 directly represses cyclin D1 by binding to three sequence elements in the cyclin D1 gene promoter, resulting in Rb hypophosphorylation and G1 accumulation in cells undergoing EMT. ChIP, promoter binding, exogenous cyclin D1 rescue, RNAi, cell cycle analysis Molecular biology of the cell High 17855508
2007 miR-200b post-transcriptionally represses ZFHX1B/ZEB2 via multiple sequence elements in the 3'-UTR; overexpression of miR-200b reduces endogenous ZEB2 and activates the E-cadherin promoter. 3'-UTR reporter assays, overexpression/inhibition of miR-200b, E-cadherin promoter activity assays RNA High 17585049
2008 ZEB2/SIP1 associates with the NuRD corepressor complex through its N-terminal domain; an MWS patient mutation in this domain abolishes NuRD recruitment and reduces transcriptional repression of the XBMP4 promoter and E-cadherin, and impairs neural induction in Xenopus. Mass spectrometry of affinity-purified complexes, Co-IP, transcriptional reporter assays, Xenopus animal cap assays Human molecular genetics High 18182442
2006 ZEB2/SIP1 induces vimentin expression in breast tumor cells and promotes cell migration; RNAi-mediated SIP1 knockdown decreases vimentin mRNA and protein, and SIP1-induced migration does not involve the β-catenin/TCF pathway. cDNA transfection, RNAi, Boyden chamber migration assay, RT-PCR, Western blot, TOP-FLASH reporter assay Oncogene Medium 16568083
2011 ZEB2/SIP1 protein stability is regulated by the F-box ubiquitin ligase Ppa (Partner of paired) through the ubiquitin-proteasome system, which also targets Twist and Snail family EMT factors. Protein stability assays, proteasome inhibitor treatment, epistasis in Xenopus, domain mapping The Journal of cell biology Medium 21727196
2013 ZEB2 cooperates with Sp1 to directly transactivate cadherin-11 and integrin α5 promoters in an Sp1-dependent but Smad- and E-box-independent manner, and ZEB2 enhances Sp1 protein stability; this ZEB2-Sp1 axis drives cancer cell invasion. ChIP, promoter reporter assays, co-immunoprecipitation, protein stability assays, invasion assays, immunofluorescence on human tumor samples Carcinogenesis Medium 24130169
2013 ZEB2/SIP1 directly activates ETS1 transcription by binding E-box sequences on the ETS1 promoter; ETS1 in turn maintains ZEB2-induced EMT and upregulates TWIST and MMP9. ChIP, luciferase reporter assays, ZEB2 knockdown/inducible expression, migration and invasion assays Molecular carcinogenesis Medium 30790340
2010 ZEB2/SIP1 limits mesendoderm-inducing effects of Activin-Nodal/SMAD2/3 signaling in human embryonic stem cells, directing cells toward neuroectoderm; Activin-Nodal signaling in turn cooperates with NANOG, OCT4, and SOX2 to control SIP1 expression. Loss-of-function and gain-of-function in hESCs, epistasis with Activin-Nodal signaling components, differentiation assays Cell stem cell Medium 20074535
2004 ZEB2/SIP1 overexpression in hepatocellular carcinoma cells suppresses E-cadherin and upregulates MMP-1, MMP-2, and MT1-MMP, thereby enhancing cancer cell invasion. Stable transfection, RT-PCR for MMPs, invasion assays, morphology assessment British journal of cancer Medium 15026811
2016 ZEB2 transcriptionally represses genes regulating myeloid differentiation and its depletion causes aberrant differentiation of AML cells; epigenetic silencing of the miR-200 family by DNA methylation controls ZEB2 expression in AML. Genome-scale shRNA screens in 17 AML cell lines and murine AML model, gene expression profiling, miR-200 methylation analysis Blood Medium 27756750
2016 Zeb2 is essential for Schwann cell differentiation and myelination; Schwann cells lacking Zeb2 fail to repress Sox2 and Ednrb (identified as Zeb2 target genes) and cannot progress through lineage differentiation. Zeb2 acts as an 'inhibitor of inhibitors' of myelination. Conditional Schwann cell-specific Zeb2 knockout in mice, peripheral nerve phenotyping, RNA-seq, target gene identification Nature neuroscience High 27294512
2013 Sip1 (Zeb2) is required cell-autonomously for cortical interneuron migration; Sip1 knockout interneurons fail to migrate to the neocortex due to elevated expression of the repulsive receptor Unc5b. Reducing Unc5b in Sip1 knockout tissue rescues the migration defect. Conditional Sip1 knockout, RNA sequencing, focal electroporation of Unc5b, genetic rescue by Unc5b knockdown Neuron High 23312517
2015 Sip1 (Zeb2) mediates axonal growth and ipsilateral cortical branching through its direct downstream effector ninein, a microtubule-binding protein that affects microtubule stability and dynamics. Conditional Sip1 knockout in postmitotic neurons, mosaic deletion, axonal tracing, ChIP to confirm ninein as direct target, ninein rescue experiments Neuron High 25741725
2016 In hypoxia, HIF-1α induces ZEB2, which directly binds the ephrinB2 promoter to repress ephrinB2 expression, thereby promoting glioma cell invasiveness; this mechanism is activated after anti-angiogenic treatment. Promoter binding assays, hypoxia treatment, HIF-1α induction, ZEB2 disruption, in vivo glioma invasion model Nature communications Medium 27470974
2017 ZEB2 directly binds to the HBV core promoter and represses HBV transcription and replication; mutation of the ZEB2 binding site in the core promoter abolishes ZEB2-mediated inhibition. ChIP, promoter reporter assays, site-directed mutagenesis, HBV replication intermediates quantification Oncotarget High 26895378
2017 ZEB2 interacts with KDM1A (LSD1), a lysine-specific demethylase, and T-ALL cells with elevated ZEB2 are critically dependent on KDM1A activity for survival. Protein interaction studies (co-IP), pharmacological KDM1A inhibition, shRNA knockdown in mouse and human T-ALL Blood Medium 28069602
2021 Cardiomyocyte-specific ZEB2 induces expression of paracrine factors Thymosin β4 (TMSB4) and Prothymosin α (PTMA), which stimulate endothelial cell migration and angiogenesis after myocardial infarction; cardiomyocyte-specific ZEB2 deletion impairs cardiac function post-MI. Cardiomyocyte-specific conditional KO and overexpression in mice, single-cell sequencing, endothelial migration assays, in vivo therapeutic ZEB2 delivery Nature communications Medium 33398012
2022 Zeb2 regulates smooth muscle cell phenotypic transition during atherosclerosis through chromatin remodeling that disrupts Notch and TGF-β signaling; SMC-specific Zeb2 loss prevents contractile-to-fibroblast-like transition and accelerates chondromyocyte formation. CRISPR-Cas9 genome and epigenome editing, single-cell ATAC-seq and RNA-seq, SMC-specific conditional KO in murine atherosclerosis model Circulation Medium 34990206
2023 ZEB2 recruits the HDAC1-NuRD complex to the CTH gene promoter to repress CSE (cystathionine γ-lyase) transcription in endothelial cells, reducing H2S production and PDI S-sulfhydration, thereby driving aortic aneurysm and dissection. Co-immunoprecipitation with mass spectrometry, ChIP, endothelial-specific HDAC1 KO mice, PDI S-sulfhydration assays, AAD mouse models Circulation High 36951067
2018 ZEB2 promotes terminal effector CD8+ T cell differentiation, while ZEB1 promotes memory formation; TGF-β induces ZEB1 in memory cells and selectively inhibits ZEB2; the miR-200 family inversely regulates ZEB1 and ZEB2 in CD8+ T cells. Conditional KO of Zeb1 and Zeb2 in CD8+ T cells, cytokine treatment, miR-200 family KO, adoptive transfer experiments The Journal of experimental medicine Medium 29449309
2016 Zeb2 inactivation in the bone marrow results in differentiation defects across multiple hematopoietic lineages and perturbs JAK-STAT and ERK signaling pathways; Zeb2 is required for M-CSF receptor expression in monocyte development and for plasmacytoid DC development. Inducible Zeb2 gene deletion, flow cytometry, global gene expression profiling, intracellular signaling analysis Blood; PNAS Medium 27683414 27930303
2019 An Nfil3-Zeb2-Id2 genetic circuit controls cDC1 development: NFIL3 represses Zeb2 expression, low Zeb2 allows Id2 to rise, and this progression commits CDPs to the cDC1 lineage; Nfil3 acts upstream of Zeb2 by genetic epistasis. Genetic epistasis in conditional KO mice, scRNA-seq, NFIL3 reporter mice, CUT&RUN, ChIP-seq Nature immunology High 31406377
2022 NFIL3 binds to a -165 kb Zeb2 enhancer at sites also bound by C/EBPα and C/EBPβ; NFIL3 represses and C/EBPs activate Zeb2 at these sites. Triple CRISPR mutation of all three NFIL3-C/EBP sites ablates Zeb2 in myeloid but not lymphoid progenitors, causing complete loss of cDC2 specification. CUT&RUN, ChIP-seq, CRISPR-Cas9 triple-site mutagenesis in vivo, lineage tracing Nature High 35732734
2024 ZEB2 drives age-associated B cell (ABC) differentiation by binding to the +20 kb MEF2B intronic enhancer, repressing MEF2B-mediated germinal center B cell differentiation. ZEB2-driven ABC differentiation requires JAK-STAT signaling. ZEB2 haploinsufficient human subjects, B cell-specific Zeb2 KO mice, ChIP/binding assays, JAK inhibitor treatment, TLR7-driven lupus model Science High 38271512
2014 FoxQ1 transactivates ZEB2 expression by directly binding to the ZEB2 promoter, driving EMT and HCC metastasis; ZEB2 knockdown suppresses FoxQ1-enhanced metastasis and its re-expression rescues it. Serial promoter deletion, site-directed mutagenesis, ChIP, ZEB2 knockdown and rescue in HCC cells, in vivo metastasis model Hepatology Medium 24005989
2021 ZEB2 regulates astrogliosis after CNS injury through an EMT-like mechanism; Zeb2os (a long non-coding RNA antisense to Zeb2) facilitates ZEB2 protein translation. Conditional Zeb2 KO in astrocytes attenuates astrogliosis, generates larger lesions, and delays motor function recovery. Conditional astrocyte-specific Zeb2 KO in spinal cord injury and stroke mouse models, Zeb2os knockdown, behavioral and histological analysis Cell reports Medium 32610135
2018 ZEB2 is highly expressed in Bergmann glia and is required for Bergmann glia specification from cerebellar radial glia; Zeb2 deletion disrupts FGF, NOTCH, and TGF-β/BMP signaling pathway components as identified by transcriptome profiling. Cerebellar radial glia-specific conditional Zeb2 KO, transcriptome profiling, immunohistochemistry, behavioral testing The Journal of neuroscience Medium 29326173
2006 VHL restoration in clear cell renal cell carcinoma cells reduces SIP1/ZEB2 and Snail expression in a HIF-dependent manner, restoring E-cadherin expression; HIF-alpha knockdown likewise increases E-cadherin, placing ZEB2 downstream of the VHL-HIF axis. VHL re-expression, HIF-alpha RNAi, hypoxia treatment, ChIP (RNA Pol II on E-cadherin promoter), VHL mutant expression Molecular and cellular biology Medium 17060462
2023 ZEB2 directly binds the ACSL4 promoter to activate ACSL4 transcription; ACSL4 protein in turn binds ZEB2 and reduces its ubiquitination to stabilize ZEB2, forming a positive feedback loop that promotes lipid storage and breast cancer metastasis. ChIP, promoter reporter assays, Co-IP, ubiquitination assays, lipid droplet quantification, in vivo metastasis model eLife Medium 38078907
2025 ZEB2 is the master transcriptional regulator of tumor-associated macrophage (TAM) programs; ZEB2 genetic ablation reprograms TAM chromatin, RNA, and protein profiles, suppresses type-I interferon response and antigen presentation, and activates immune suppression. In vivo ZEB2 targeting reprograms TAMs and mobilizes T cell anti-tumor responses. Integrative scRNA-seq with CRISPR screen, gene perturbation network, conditional Zeb2 KO in TAMs, in vivo tumor models Cancer cell Medium 40215981
2018 p53 binds the MIR30A promoter and induces transcription of miR-30a-5p and -3p; both target ZEB2 3'-UTR, placing ZEB2 downstream of p53 via miR-30a, thereby restraining EMT, tumor invasion, and distal metastasis in breast cancer. ChIP for p53 on MIR30A promoter, 3'UTR reporter assays, invasion assays, in vivo zebrafish/mouse metastasis models Cell death and differentiation Medium 29666469
2018 Silencing of the Zeb2-NAT (natural antisense transcript overlapping the Zeb2 locus) reduces Zeb2 protein levels and enhances somatic cell reprogramming; Zeb2-NAT knockdown in ES cells maintains pluripotency upon differentiation stimuli, identifying Zeb2-NAT as a translational regulator of Zeb2 protein. LNA GapmeR knockdown of Zeb2-NAT, Western blot, reprogramming efficiency assays, ES cell pluripotency assays Nature communications Medium 29311544
2021 MEF2A directly binds the ZEB2 and CTNNB1 (β-catenin) promoters to transactivate their expression in colorectal cancer, simultaneously inducing EMT and activating Wnt/β-catenin signaling. ChIP, promoter reporter assays, MEF2A overexpression and knockdown, invasion and proliferation assays Oncogene Medium 33863999
2022 Endothelial Zeb2 maintains liver sinusoidal endothelial cell identity and regulates LSEC-hepatic stellate cell communication; EC-specific Zeb2 KO increases capillarization and HSC activation, while EC-specific Zeb2 overexpression attenuates CCl4-induced liver fibrosis. EC-specific conditional KO and overexpression in mice, RNA-seq of liver EC, CCl4 fibrosis model, HSC activation markers Cardiovascular research Medium 33909875

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nature cell biology 3202 18376396
2001 The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Molecular cell 1160 11430829
2008 A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer research 902 18829540
1997 The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell 567 9323130
2002 Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. The American journal of pathology 488 12414534
2001 Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nature genetics 273 11279515
2004 Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. British journal of cancer 250 15026811
2006 VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Molecular and cellular biology 208 17060462
2001 Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease. Human molecular genetics 196 11448942
2007 Direct repression of cyclin D1 by SIP1 attenuates cell cycle progression in cells undergoing an epithelial mesenchymal transition. Molecular biology of the cell 183 17855508
2012 ZEB2 mediates multiple pathways regulating cell proliferation, migration, invasion, and apoptosis in glioma. PloS one 154 22761708
2012 MicroRNA-200b regulates cell proliferation, invasion, and migration by directly targeting ZEB2 in gastric carcinoma. Annals of surgical oncology 151 22311119
2007 miR-200b mediates post-transcriptional repression of ZFHX1B. RNA (New York, N.Y.) 150 17585049
2006 Regulation of vimentin by SIP1 in human epithelial breast tumor cells. Oncogene 147 16568083
2014 Forkhead box Q1 promotes hepatocellular carcinoma metastasis by transactivating ZEB2 and VersicanV1 expression. Hepatology (Baltimore, Md.) 134 24005989
2007 Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down-regulation of E-cadherin. The Journal of pathology 132 17299729
2018 ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8+ T cell fates. The Journal of experimental medicine 126 29449309
2011 The F-box protein Ppa is a common regulator of core EMT factors Twist, Snail, Slug, and Sip1. The Journal of cell biology 125 21727196
2016 Zeb2 is essential for Schwann cell differentiation, myelination and nerve repair. Nature neuroscience 122 27294512
2024 The transcription factor ZEB2 drives the formation of age-associated B cells. Science (New York, N.Y.) 113 38271512
2010 SIP1 mediates cell-fate decisions between neuroectoderm and mesendoderm in human pluripotent stem cells. Cell stem cell 112 20074535
2013 Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: association with an aggressive tumour phenotype. Breast cancer research and treatment 110 23412770
2013 Directed migration of cortical interneurons depends on the cell-autonomous action of Sip1. Neuron 108 23312517
2019 An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development. Nature immunology 95 31406377
2022 Ablation of cDC2 development by triple mutations within the Zeb2 enhancer. Nature 91 35732734
2019 The crucial role of ZEB2: From development to epithelial-to-mesenchymal transition and cancer complexity. Journal of cellular physiology 87 30773635
2018 A p53/miR-30a/ZEB2 axis controls triple negative breast cancer aggressiveness. Cell death and differentiation 83 29666469
2021 Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner. Nature communications 82 33398012
2000 The exon 2b region of the spinal muscular atrophy protein, SMN, is involved in self-association and SIP1 binding. Human molecular genetics 81 11092763
2008 Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex. Human molecular genetics 80 18182442
2003 Further delineation of the phenotype associated with heterozygous mutations in ZFHX1B. American journal of medical genetics. Part A 80 12784289
2016 Transcription factor Zeb2 regulates commitment to plasmacytoid dendritic cell and monocyte fate. Proceedings of the National Academy of Sciences of the United States of America 76 27930303
2023 Endothelial HDAC1-ZEB2-NuRD Complex Drives Aortic Aneurysm and Dissection Through Regulation of Protein S-Sulfhydration. Circulation 70 36951067
2016 The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia. Blood 68 27756750
2016 EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance. Nature communications 66 27470974
2016 The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling. Blood 63 27683414
2006 deltaEF1 and SIP1 are differentially expressed and have overlapping activities during Xenopus embryogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 63 16518800
2022 ZEB2 Shapes the Epigenetic Landscape of Atherosclerosis. Circulation 60 34990206
2016 Downregulation of ZEB2-AS1 decreased tumor growth and metastasis in hepatocellular carcinoma. Molecular medicine reports 59 27748842
2018 MiR-454-3p and miR-374b-5p suppress migration and invasion of bladder cancer cells through targetting ZEB2. Bioscience reports 57 30352837
2017 LncRNA ZFAS1 promotes growth and metastasis by regulating BMI1 and ZEB2 in osteosarcoma. American journal of cancer research 56 28744396
2013 Genome-wide association study identifies ZFHX1B as a susceptibility locus for severe myopia. Human molecular genetics 55 23933737
2018 Role of Zeb2/Sip1 in neuronal development. Brain research 54 30266271
2015 MicroRNA-129-5p modulates epithelial-to-mesenchymal transition by targeting SIP1 and SOX4 during peritoneal dialysis. Laboratory investigation; a journal of technical methods and pathology 54 25961171
2013 ZEB2-Sp1 cooperation induces invasion by upregulating cadherin-11 and integrin α5 expression. Carcinogenesis 51 24130169
2018 Silencing of the lncRNA Zeb2-NAT facilitates reprogramming of aged fibroblasts and safeguards stem cell pluripotency. Nature communications 49 29311544
2017 Ets1 and ESE1 reciprocally regulate expression of ZEB1/ZEB2, dependent on ERK1/2 activity, in breast cancer cells. Cancer science 49 28247944
2015 Sip1 downstream Effector ninein controls neocortical axonal growth, ipsilateral branching, and microtubule growth and stability. Neuron 48 25741725
2020 Zeb2 Is a Regulator of Astrogliosis and Functional Recovery after CNS Injury. Cell reports 47 32610135
2017 LncRNA ZEB2-AS1 promotes bladder cancer cell proliferation and inhibits apoptosis by regulating miR-27b. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 47 28992472
2015 The Chaperone Activity of the Developmental Small Heat Shock Protein Sip1 Is Regulated by pH-Dependent Conformational Changes. Molecular cell 47 26009280
2020 Zeb2 drives invasive and microbiota-dependent colon carcinoma. Nature cancer 46 35121975
2021 MEF2A transcriptionally upregulates the expression of ZEB2 and CTNNB1 in colorectal cancer to promote tumor progression. Oncogene 45 33863999
2013 Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development. Mechanisms of development 44 24161570
2016 microRNA-145 modulates epithelial-mesenchymal transition and suppresses proliferation, migration and invasion by targeting SIP1 in human cervical cancer cells. Cellular oncology (Dordrecht, Netherlands) 42 27933466
2024 Age-associated CD4+ T cells with B cell-promoting functions are regulated by ZEB2 in autoimmunity. Science immunology 40 38330141
2014 The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations. American journal of medical genetics. Part A 37 24715670
2010 Genetic interaction between Sox10 and Zfhx1b during enteric nervous system development. Developmental biology 37 20206619
2022 Endothelial Zeb2 preserves the hepatic angioarchitecture and protects against liver fibrosis. Cardiovascular research 36 33909875
2009 Identification of the role of Smad interacting protein 1 (SIP1) in glioma. Journal of neuro-oncology 35 19806322
2001 SIP1 (Smad interacting protein 1) and deltaEF1 (delta-crystallin enhancer binding factor) are structurally similar transcriptional repressors. The Journal of bone and joint surgery. American volume 34 11263664
2021 DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition. The Journal of allergy and clinical immunology 33 33957165
2009 Clinicopathological significance of Sip1-associated epithelial mesenchymal transition in non-small cell lung cancer progression. Anticancer research 33 19846957
2023 A positive feedback loop between ZEB2 and ACSL4 regulates lipid metabolism to promote breast cancer metastasis. eLife 32 38078907
2021 ZEB2, the Mowat-Wilson Syndrome Transcription Factor: Confirmations, Novel Functions, and Continuing Surprises. Genes 32 34356053
2018 Transcriptional Regulator ZEB2 Is Essential for Bergmann Glia Development. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 29326173
2010 Novel monoclonal antibodies detect Smad-interacting protein 1 (SIP1) in the cytoplasm of human cells from multiple tumor tissue arrays. Experimental and molecular pathology 32 20515682
2020 MicroRNA-140 Represses Esophageal Cancer Progression via Targeting ZEB2 to Regulate Wnt/β-Catenin Pathway. The Journal of surgical research 31 32862055
2018 Hypoxia induces ZEB2 in podocytes: Implications in the pathogenesis of proteinuria. Journal of cellular physiology 30 30238984
2011 Coexpression of hypoxia-inducible factor-2α, TWIST2, and SIP1 may correlate with invasion and metastasis of salivary adenoid cystic carcinoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 29 22103974
2006 Atypical ZFHX1B mutation associated with a mild Mowat-Wilson syndrome phenotype. American journal of medical genetics. Part A 29 16532472
2019 ETS1 is coexpressed with ZEB2 and mediates ZEB2-induced epithelial-mesenchymal transition in human tumors. Molecular carcinogenesis 28 30790340
2019 Association of the ZC3H11B, ZFHX1B and SNTB1 genes with myopia of different severities. The British journal of ophthalmology 26 31300455
2017 MiR-590-3p suppresses epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma by inhibiting SIP1 expression. Oncotarget 26 28423728
2021 Differential usage of transcriptional repressor Zeb2 enhancers distinguishes adult and embryonic hematopoiesis. Immunity 25 34004142
2006 Identification and characterization of the carboxy-terminal region of Sip-1, a novel autoantigen in Behçet's disease. Arthritis research & therapy 25 16611372
2019 ZEB2 and LMO2 drive immature T-cell lymphoblastic leukemia via distinct oncogenic mechanisms. Haematologica 24 30679322
2017 E-cadherin and ZEB2 modulate trophoblast cell differentiation during placental development in pigs. Reproduction (Cambridge, England) 24 28912304
2013 Differential expression of transcription factors Snail, Slug, SIP1, and Twist in ameloblastoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 24 23560539
2013 Splice variants of the SIP1 transcripts play a role in nodule organogenesis in Lotus japonicus. Plant molecular biology 23 23494209
2020 TCF4 promotes colorectal cancer drug resistance and stemness via regulating ZEB1/ZEB2 expression. Protoplasma 22 31933004
2018 miR-146 promotes HBV replication and expression by targeting ZEB2. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 29902868
2017 MicroRNA-192 regulates hypertrophic scar fibrosis by targeting SIP1. Journal of molecular histology 22 28884252
2012 Smad interacting protein 1 (SIP1) is associated with peritoneal carcinomatosis in intestinal type gastric cancer. Clinical & experimental metastasis 22 23143680
2018 TRIM37 promotes cell invasion and metastasis by regulating SIP1-mediated epithelial-mesenchymal transition in gastric cancer. OncoTargets and therapy 21 30573971
2017 Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia. Blood 21 28069602
2015 De novo inbred heterozygous Zeb2/Sip1 mutant mice uniquely generated by germ-line conditional knockout exhibit craniofacial, callosal and behavioral defects associated with Mowat-Wilson syndrome. Human molecular genetics 21 26319231
2025 ZEB2 is a master switch controlling the tumor-associated macrophage program. Cancer cell 20 40215981
2021 Puerarin Prevents Acute Liver Injury via Inhibiting Inflammatory Responses and ZEB2 Expression. Frontiers in pharmacology 20 34421621
2021 Two aquaporins, SIP1;1 and PIP1;2, mediate water transport for pollen hydration in the Arabidopsis pistil. Plant biotechnology (Tokyo, Japan) 19 34177327
2020 The Lnc LINC00461/miR-30a-5p facilitates progression and malignancy in non-small cell lung cancer via regulating ZEB2. Cell cycle (Georgetown, Tex.) 19 32106756
2013 SIP1 expression patterns in brain investigated by generating a SIP1-EGFP reporter knock-in mouse. Genesis (New York, N.Y. : 2000) 19 24243579
2020 HIPK3 Circular RNA Promotes Metastases of HCC Through Sponging miR-338-3p to Induce ZEB2 Expression. Digestive diseases and sciences 18 33247421
2016 ZEB2 inhibits HBV transcription and replication by targeting its core promoter. Oncotarget 18 26895378
2010 Sip1, the Drosophila orthologue of EBP50/NHERF1, functions with the sterile 20 family kinase Slik to regulate Moesin activity. Journal of cell science 18 20215404
2009 Retroviral insertional mutagenesis identifies Zeb2 activation as a novel leukemogenic collaborating event in CALM-AF10 transgenic mice. Blood 18 20007546
1998 Sip1, a novel RS domain-containing protein essential for pre-mRNA splicing. Molecular and cellular biology 18 9447963
2019 ZEB2-AS1 Accelerates Epithelial/Mesenchymal Transition Through miR-1205/CRKL Pathway in Colorectal Cancer. Cancer biotherapy & radiopharmaceuticals 17 31755734
2015 Expression of SIP1 is strongly correlated with LDHA and shows a significantly poor outcome in gastric cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 17 25913622
2019 ZEB2 in T-cells and T-ALL. Advances in biological regulation 16 31383581