Affinage

TCF4

Transcription factor 4 · UniProt P15884

Length
667 aa
Mass
71.3 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TCF4 (E2-2/ITF2) is a class I basic helix-loop-helix (bHLH) E-protein transcription factor that binds E-box DNA as a homo-oligomer or as heterodimers with tissue-specific bHLH partners, with its basic region recognizing E-box flanking sequences and preferentially engaging 5-carboxylcytosine via residues such as Arg576 that are mutated in Pitt-Hopkins syndrome (PMID:1312219, PMID:31081034). Through its bHLH domain it partners with proneural and lineage factors (HASH-1, myogenin, E12, HEB) and with the inhibitory HLH protein Id1 to set context-specific transcriptional outputs (PMID:1312219, PMID:10903890, PMID:20231428). In the hematopoietic system TCF4 acts as a master lineage regulator: it is essential for plasmacytoid dendritic cell (pDC) specification, directly activating pDC genes SpiB, Irf7, and Irf8, and continuously enforces pDC identity against the default cDC fate, with a long isoform and a downstream enhancer establishing a positive-feedback loop sensitive to BET inhibition (PMID:18854153, PMID:21145760, PMID:27986456). It also contributes more broadly to lymphoid specification with HEB, early T- and B-cell development, conventional DC2A development, and GM-CSF-driven macrophage differentiation (PMID:17082585, PMID:18384878, PMID:30936870, PMID:22099176, PMID:40702338). In neural development TCF4 functions as a transcriptional activator required for cortical neuron specification, commissure and corpus callosum formation, and midline glia, cooperating with SOX11 and lying downstream of Zac1 in a Zac1→Tcf4→p57(Kip2) cell-cycle arrest axis; its haploinsufficiency causes hippocampal LTP and memory deficits through an HDAC2-dependent mechanism, and postnatal reinstatement of Tcf4 reverses Pitt-Hopkins-like phenotypes (PMID:24396065, PMID:32474139, PMID:34184026, PMID:27568567, PMID:35535852). Independently, TCF4 serves as a Wnt effector through β-catenin, occupying thousands of distal A-C/G-A/T-T-C-A-A-A-G enhancer elements and integrating a large set of co-regulators—positively (Kindlin-2, TRIB3, CHAF1A, TEAD4) and negatively (MAD2B, Daxx)—to drive target genes including MYC and CCND1 (PMID:19443654, PMID:16569639, PMID:18268006, PMID:22699938, PMID:30365932, PMID:28051067, PMID:30449701). Its stability and activity are tuned by sumoylation at Lys297 (via PIASy, opposed by Axam; also via UHRF2) and by Parkin-mediated ubiquitination that is blocked by NF-κB p65 binding (PMID:12727872, PMID:32372448, PMID:37185280). Intronic CTG18.1 trinucleotide repeat expansion in TCF4 produces toxic nuclear CUG RNA foci that sequester splicing factors in corneal endothelium, the genetic basis of Fuchs endothelial corneal dystrophy (PMID:29325021, PMID:25722209).

Mechanistic history

Synthesis pass · year-by-year structured walk · 36 steps
  1. 1992 Medium

    Established TCF4/ITF2 as a functional E-protein bHLH transcription factor, defining its core biochemical activity of E-box binding and partner-dependent dimerization.

    Evidence In vitro EMSA, hetero-oligomerization with myogenin/E12/HEB, and luciferase activation

    PMID:1312219

    Open questions at the time
    • No cellular context for which partnerships dominate in vivo
    • No structural basis for partner selection
  2. 1993 Medium

    Showed TCF4 participates in developmentally regulated E-box complexes alongside E2A, indicating stage-specific complex composition governs B-lineage gene control.

    Evidence Antibody supershift of endogenous immunoglobulin enhancer complexes in pre-B vs mature B cells

    PMID:8497267

    Open questions at the time
    • Did not define direct target genes
    • Functional consequence of complex switching not tested
  3. 2000 Medium

    Identified a neural heterodimer partner (HASH-1), linking TCF4 to proneural transcription programs.

    Evidence Yeast two-hybrid, co-IP, EMSA, and reporter assays in neuroblastoma cells

    PMID:10903890

    Open questions at the time
    • Endogenous target genes of the complex not identified
    • In vivo relevance not tested
  4. 2001 Medium

    Defined TCF4 as a transcriptional repressor in differentiation contexts (melanocyte pigmentation, osteopontin), broadening its role beyond activation.

    Evidence Sense/antisense overexpression, reporter assays, EMSA of CAAAG-element complexes

    PMID:11382753 PMID:11454716

    Open questions at the time
    • Mechanism of repression (co-repressor recruitment) undefined
    • Single-lab phenotypes
  5. 2003 High

    Revealed sumoylation at Lys297 as a post-translational switch coupling TCF4 to β-catenin-dependent Wnt transcription.

    Evidence Sumoylation assays, PIASy/Axam manipulation, K297R mutagenesis, reporter assays, PML-body co-localization

    PMID:12727872

    Open questions at the time
    • Genome-wide consequences of sumoylation not mapped
    • Which target genes depend on this modification unclear
  6. 2006 Medium

    Connected TCF4 to early B-lymphoid expansion and follicular-vs-marginal-zone fate, establishing a hematopoietic developmental role.

    Evidence Fetal liver reconstitution into Rag-deficient mice with flow cytometry

    PMID:17082585

    Open questions at the time
    • Direct B-lineage target genes not defined
    • Mechanism of fate skewing unknown
  7. 2006 Medium

    Identified Daxx as a nuclear repressor of TCF4 DNA binding, linking TCF4 activity to cyclin D1, Hath-1, and cell-cycle control.

    Evidence Yeast two-hybrid, co-IP, EMSA, reporter assays, cell-cycle analysis in colon cancer cells

    PMID:16569639

    Open questions at the time
    • Endogenous physiological setting unclear
    • Single-lab interaction
  8. 2008 High

    Defined the genome-wide TCF4 cistrome in Wnt-active cells, showing it occupies distal conserved enhancers acting in a β-catenin-dependent manner.

    Evidence ChIP-chip in LS174T colorectal cells, motif discovery, enhancer reporter validation

    PMID:18268006

    Open questions at the time
    • Co-factor occupancy at each site not resolved
    • Cell-type specificity of the cistrome untested
  9. 2008 High

    Established TCF4 as the essential, specific master regulator of pDC development, directly activating pDC identity genes.

    Evidence Conditional and inducible KO mice, ChIP/reporter target validation, IFN-response phenotyping

    PMID:18854153

    Open questions at the time
    • Upstream signals inducing TCF4 in pDC precursors not defined here
    • Co-factors at pDC genes not mapped
  10. 2008 Medium

    Linked β-catenin/TCF4 transcription to alternative splicing via direct upregulation of SRp20, extending Wnt output to RNA processing.

    Evidence Dominant-negative TCF4, activated β-catenin, SRp20 promoter reporter, CD44 splicing assays

    PMID:18952824

    Open questions at the time
    • Direct TCF4 binding to SRp20 promoter not shown
    • Breadth of splicing changes limited
  11. 2008 Medium

    Placed TCF4 within early T-cell development, cooperating with E2A and HEB at the DN3 checkpoint.

    Evidence E2-2 KO thymocyte profiling, flow cytometry, pre-Tα expression analysis

    PMID:18384878

    Open questions at the time
    • Direct vs redundant role versus E2A/HEB not separated
    • Target genes beyond pre-Tα unknown
  12. 2009 High

    Identified MAD2B as a direct negative regulator that blocks TCF4 DNA binding, controlling EMT through Slug/E-cadherin.

    Evidence Yeast two-hybrid, co-IP, EMSA, ChIP, reporter assays in colorectal cells

    PMID:19443654

    Open questions at the time
    • Structural basis of DNA-binding inhibition unknown
    • In vivo relevance not tested
  13. 2009 Medium

    Mapped the bHLH basic domain as a Pitt-Hopkins mutational hotspot, showing mutations impair homodimerization more than heterodimerization.

    Evidence Luciferase reporter assays with patient-derived mutations and cohort analysis

    PMID:19235238

    Open questions at the time
    • Single primary method
    • Quantitative dimerization not measured biochemically here
  14. 2010 High

    Demonstrated TCF4 actively maintains mature pDC fate post-development by opposing the default cDC program genome-wide.

    Evidence Inducible deletion in mature pDCs, genome-wide ChIP, expression profiling

    PMID:21145760

    Open questions at the time
    • Mechanism opposing cDC genes (repression machinery) not defined
    • Feedback maintaining TCF4 not yet mapped
  15. 2010 Medium

    Revealed an anti-angiogenic role for TCF4 in endothelial cells, antagonized by Id1 through HLH-domain interaction.

    Evidence Matrigel plug, EC functional assays, HLH-domain mutagenesis, VEGFR2 promoter reporter

    PMID:20231428

    Open questions at the time
    • Direct VEGFR2 promoter binding not shown
    • Single-lab in vivo model
  16. 2011 Medium

    Extended TCF4 function to myeloid (macrophage) and muscle fiber-type development, integrating it into GM-CSF/Wnt and fibroblast-derived programs.

    Evidence Retroviral Tcf4/β-catenin overexpression with colony assays; Tcf4Cre fibroblast manipulation and conditional KO with fiber-type analysis

    PMID:21177349 PMID:22099176

    Open questions at the time
    • Direct TCF4 targets in each tissue undefined
    • Intrinsic vs extrinsic contributions partially separated
  17. 2012 Medium

    Mechanistically linked Pitt-Hopkins bHLH mutations to defects in subnuclear localization, dimerization, and neuronal target gene transactivation (NRXN1β, CNTNAP2).

    Evidence HTRF dimerization assays, localization imaging, promoter reporter assays

    PMID:22777675

    Open questions at the time
    • Context-dependence of transactivation deficits not fully resolved
    • Endogenous target regulation not tested
  18. 2012 Medium

    Identified Kindlin-2 as a component of a β-catenin/TCF4 tripartite complex driving Axin2 and invasion, expanding the Wnt co-regulator network.

    Evidence Co-IP, ChIP at Axin2 promoter, reporter and invasion assays

    PMID:22699938

    Open questions at the time
    • Direct Kindlin-2–TCF4 contact vs β-catenin-bridged unclear
    • Single-lab
  19. 2014 Medium

    Established Zac1→Tcf4→p57(Kip2) as a transcriptional axis controlling cell-cycle arrest in neuronal progenitors, placing TCF4 downstream of an upstream activator.

    Evidence ChIP for Zac1 at the Tcf4 locus, reporter assays, Tcf4 overexpression, cell-cycle analysis

    PMID:24396065

    Open questions at the time
    • Direct TCF4 binding to p57 locus not shown here
    • In vivo requirement not tested
  20. 2014 Medium

    Showed ITF2/TCF4 can antagonize the β-catenin-TCF4 complex by competing for β-catenin, acting as a tumor suppressor in colorectal cancer.

    Evidence Co-IP competition, TOPFLASH reporter, shRNA, stable overexpression, xenografts

    PMID:24846398

    Open questions at the time
    • Reconciliation of activator vs competitor roles unclear
    • Isoform identity in competition not fully defined
  21. 2015 Medium

    Defined a TCF3-to-TCF4 exchange at the MYC 3' WRE controlling MYC during cell-cycle re-entry, clarifying TCF factor dynamics.

    Evidence ChIP, shRNA TCF3 depletion, GSK3β inhibition, MYC and cell-cycle readouts

    PMID:25659031

    Open questions at the time
    • Mechanism driving factor exchange beyond GSK3β unclear
    • Single-locus focus
  22. 2015 Medium

    Demonstrated that intronic CTG18.1 expansion produces nuclear CUG RNA foci in patient corneal endothelium, implicating toxic RNA rather than haploinsufficiency in FECD.

    Evidence FISH for RNA foci with controls and qRT-PCR of TCF4 expression

    PMID:25722209

    Open questions at the time
    • Direct demonstration of splicing-factor sequestration not yet shown here
    • Causality vs correlation in patient tissue
  23. 2016 High

    Resolved TCF4 isoform requirements and a downstream enhancer feedback loop in pDC differentiation, with BET-inhibitor sensitivity.

    Evidence Isoform-specific KO mice, enhancer deletion, in vitro differentiation, BET inhibition

    PMID:27986456

    Open questions at the time
    • Trans-factors activating the enhancer not identified
    • Isoform-specific cistromes not separated
  24. 2016 Medium

    Identified TCF4 as the master regulator of the BPDCN oncogenic program and super-enhancer network, providing a therapeutic vulnerability via BET inhibition.

    Evidence RNAi screen, shRNA, expression profiling, BET inhibitors, xenografts

    PMID:27846392

    Open questions at the time
    • Direct super-enhancer targets list incomplete
    • Single-lab
  25. 2016 Medium

    Linked TCF4 haploinsufficiency to hippocampal LTP and memory deficits acting through an HDAC2-dependent epigenetic mechanism, suggesting a therapeutic axis.

    Evidence Tcf4+/- mice, electrophysiology, behavior, HDAC inhibition and Hdac2 knockdown, mRNA/methylome sequencing

    PMID:27568567

    Open questions at the time
    • Direct TCF4-HDAC2 regulatory link mechanism unclear
    • Which target genes mediate memory deficits not pinned
  26. 2017 Medium

    Showed TEAD4 forms a complex with TCF4 targeted by VGLL4, mechanistically connecting Wnt and Hippo-YAP signaling at the transcription-factor level.

    Evidence Co-IP, ChIP, reporter assays, VGLL4-mimicking peptide, in vivo CRC model

    PMID:28051067

    Open questions at the time
    • Direct TEAD4–TCF4 contact surface undefined
    • Generality beyond CRC unknown
  27. 2018 Medium

    Identified TRIB3 and CHAF1A as positive co-regulators that enhance TCF4/β-catenin promoter recruitment and target gene expression (MYC, CCND1).

    Evidence Co-IP, ChIP at Wnt target promoters, reporter assays, peptide disruption, xenografts

    PMID:30365932 PMID:30449701

    Open questions at the time
    • Direct vs bridged interactions not fully resolved
    • Tissue specificity of co-activation unclear
  28. 2019 High

    Provided structural basis for TCF4 recognizing 5-carboxylcytosine at E-box flanks, showing Pitt-Hopkins basic-region arginines (R569, R576) mediate this modified-base reading.

    Evidence Crystal structures of bHLH with unmodified and 5caC DNA, binding assays, disease-residue mutagenesis

    PMID:31081034

    Open questions at the time
    • Genome-wide impact of 5caC reading on target selection unknown
    • Functional role in vivo untested
  29. 2019 Medium

    Established TCF4 as an oncogenic driver in ABC-like DLBCL via 18q21.2 gains, occupying IGHM/MYC enhancers and creating synthetic-lethal vulnerability, and as master regulator of the melanoma mesenchymal program.

    Evidence Copy-number profiling, ChIP, dominant-negative and BET PROTAC, xenografts; single-cell multi-omics with TCF4 perturbation in melanoma

    PMID:31217338 PMID:38181739

    Open questions at the time
    • Co-factor dependencies in lymphoma vs melanoma differ and are incompletely mapped
    • Single-lab studies
  30. 2019 Medium

    Demonstrated E2-2 and HEB are jointly required for lymphoid lineage specification, defining the E-protein combination controlling early lymphopoiesis.

    Evidence E2-2/HEB double conditional KO mice, progenitor and mature immune profiling, adoptive transfer

    PMID:30936870

    Open questions at the time
    • Direct lymphoid target genes not defined
    • Relative E2-2 vs HEB contribution unresolved
  31. 2020 Medium

    Defined TCF4 as a transcriptional activator essential for cortical neuron specification, commissure and corpus callosum formation, and midline glia.

    Evidence Conditional KO mice, immunohistochemistry, RNA-seq of E14.5 cortex

    PMID:32474139

    Open questions at the time
    • Direct vs indirect downregulated targets not separated
    • Partner dependence at neural targets unmapped
  32. 2020 Medium

    Showed UHRF2 sumoylates and stabilizes Tcf4 in a feedforward loop sustaining Wnt signaling in intestinal tumors, and confirmed CUG RNA foci sequester splicing factors with ASO reversibility in FECD.

    Evidence Co-IP, sumoylation assays, Uhrf2-null ApcMin mice (Wnt); FISH, splicing analysis, ASO rescue in patient cells and ex vivo corneas (FECD)

    PMID:29325021 PMID:32372448

    Open questions at the time
    • UHRF2 sumoylation site on TCF4 not mapped relative to Lys297
    • Long-term therapeutic durability of ASO not assessed
  33. 2021 Medium

    Distinguished embryonic from adult TCF4 functions in neurons and identified SOX11 as a cooperating partner controlling commissure formation, with distinct adult target programs (plasma membrane, ciliary genes).

    Evidence Adult conditional KO with electrophysiology, morphology, and transcriptomics; scRNA-seq regulon analysis and co-IP

    PMID:34184026 PMID:34564703

    Open questions at the time
    • Direct SOX11–TCF4 binding mode undefined
    • Mechanism of stage-specific target switching unknown
  34. 2022 Medium

    Showed postnatal reinstatement of Tcf4 reverses Pitt-Hopkins-like behavioral, EEG, and gene-expression deficits, establishing reversibility and therapeutic feasibility.

    Evidence Conditional Tcf4 mouse model with viral gene reinstatement, behavior, EEG, expression analysis

    PMID:35535852

    Open questions at the time
    • Window of reversibility not fully delineated
    • Cell-type-specific contributions to rescue unclear
  35. 2023 High

    Defined post-translational control of ITF2/TCF4 stability: NF-κB p65 binds the N-terminus to block Parkin-mediated ubiquitination, with loss promoting colitis-associated cancer.

    Evidence Co-IP, ubiquitination assays, conditional intestinal KO, AOM/DSS model, stability assays

    PMID:37185280

    Open questions at the time
    • Parkin ubiquitination site on TCF4 not mapped
    • Interplay with sumoylation-based stabilization unresolved
  36. 2025 Medium

    Extended TCF4's dendritic-cell role to a CD7+CD11blo DC2A conventional DC lineage arising from pre-DC2 progenitors, refining its lineage map.

    Evidence Single-cell sequencing, conditional KO mice, fate-mapping, adoptive transfer

    PMID:40702338

    Open questions at the time
    • Direct DC2A target genes not defined
    • Relationship to pDC program unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TCF4 selects among its many co-regulators and bHLH partners to specify distinct transcriptional outputs across lineages, and how its post-translational modifications integrate to govern this, remains unresolved.
  • No integrated map linking partner choice to target selection across tissues
  • Crosstalk between sumoylation, ubiquitination, and DNA-binding not resolved
  • 5caC-reading consequences for in vivo target selection unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 6 R-HSA-1266738 Developmental Biology 5 R-HSA-74160 Gene expression (Transcription) 4
Complex memberships
β-catenin/TCF4 Wnt transcription complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 E2-2/TCF4 is an essential and specific transcriptional regulator of plasmacytoid dendritic cell (pDC) development; constitutive or inducible deletion of E2-2 in mice blocked pDC development and abolished IFN response to unmethylated DNA. E2-2 directly activated multiple pDC-enriched genes including SpiB, Irf8, and Irf7. Conditional knockout mice, inducible deletion, direct target gene activation by ChIP/reporter assays, loss-of-function with defined cellular and molecular phenotype Cell High 18854153
2010 Deletion of E2-2/TCF4 from mature peripheral pDCs caused their spontaneous differentiation into cells with classical dendritic cell (cDC) properties, including loss of pDC markers and acquisition of cDC signature genes. Genome-wide ChIP revealed direct binding of E2-2 to key pDC-specific, lymphoid, and certain cDC-enriched genes, indicating E2-2 actively maintains pDC cell fate by opposing the default cDC fate. Inducible deletion in mature pDCs, genome-wide chromatin immunoprecipitation (ChIP), gene expression profiling, flow cytometry Immunity High 21145760
2016 TCF4 comprises two transcriptional isoforms, both required for optimal pDC development. The long TCF4 isoform is expressed specifically in pDCs; its deletion impaired pDC development and expanded non-canonical CD8+ cDCs. A conserved downstream enhancer is required for TCF4 upregulation during pDC differentiation, revealing a positive feedback loop. TCF4 expression and pDC differentiation were selectively sensitive to BET protein inhibition. Isoform-specific knockout mice, in vitro pDC differentiation, enhancer deletion, BET inhibitor treatment, gene expression profiling Immunity High 27986456
2003 TCF4 is sumoylated at endogenous levels, with Lys297 identified as a sumoylation site. PIASy (SUMO E3 ligase) enhanced TCF4 sumoylation and beta-catenin-dependent transcriptional activity, while Axam (desumoylation enzyme) inhibited it. TCF4, SUMO-1, and PIASy co-localize in the nucleus within PML bodies. Mutation K297R reduced PIASy/beta-catenin-dependent activation, establishing that sumoylation of TCF4 is involved in beta-catenin-dependent gene expression in the Wnt pathway. Co-immunoprecipitation, sumoylation assays, PIASy overexpression, Axam siRNA knockdown, luciferase reporter, site-directed mutagenesis (K297R), co-localization The EMBO journal High 12727872
1993 E2-2/TCF4 and E2A polypeptides are both present in B-cell-specific immunoglobulin enhancer E2-box binding complexes. In pre-B cells, complexes contain both E2-2 and E2A subunits; in mature B cells only E2A products are present, indicating differential developmental expression governs complex composition. Monoclonal antibody-based immunoprecipitation/supershift of E2-box binding complexes, Western blotting Molecular and cellular biology Medium 8497267
1992 ITF2/E2-2 (TCF4) binds E-box sequences as homo-oligomers and forms hetero-oligomers with myogenin, E12, and HEB. Hetero-oligomerization with myogenin modulates DNA-binding specificity and binding off-rates. ITF2 can activate gene expression, establishing it as a functional E-protein class bHLH transcription factor. In vitro DNA binding assays, gel shift/EMSA, hetero-oligomerization assays, luciferase transcriptional activation Molecular and cellular biology Medium 1312219
2009 MAD2B directly interacts with TCF4 (identified by yeast two-hybrid and confirmed by co-immunoprecipitation). The MAD2B–TCF4 interaction abolished the DNA-binding ability of TCF4 and blocked TCF4-mediated transcriptional activation (TOPFLASH assay). MAD2B knockdown in colorectal cancer cells led to epithelial-mesenchymal transdifferentiation by enhancing TCF4 binding to the Slug promoter and repressing E-cadherin expression. Yeast two-hybrid, co-immunoprecipitation, EMSA, TOPFLASH reporter, siRNA knockdown, chromatin immunoprecipitation, E-cadherin promoter reporter The Journal of biological chemistry High 19443654
2006 Daxx was isolated as a TCF4-interacting protein by yeast two-hybrid and confirmed by co-immunoprecipitation. In the nucleus, Daxx reduced TCF4 DNA-binding activity and repressed TCF4 transcriptional activity, altering expression of downstream targets cyclin D1 and Hath-1 and inducing G1 phase arrest in colon cancer cells. Yeast two-hybrid, co-immunoprecipitation, EMSA, transcriptional reporter assays, flow cytometry cell cycle analysis The Journal of biological chemistry Medium 16569639
2000 E2-2/TCF4 interacts with HASH-1 (human MASH-1) in both yeast and mammalian cells (confirmed by yeast two-hybrid and co-immunoprecipitation). The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro and transactivates an E-box-containing reporter in vivo, indicating E2-2 forms a functional bHLH heterodimer with the proneural factor HASH-1 in neuroblastoma cells. Yeast two-hybrid, co-immunoprecipitation in mammalian cells, EMSA, luciferase reporter assay Biochemical and biophysical research communications Medium 10903890
2010 E2-2/TCF4 inhibits endothelial cell (EC) activation, migration, network formation, and proliferation, and suppresses in vivo angiogenesis (Matrigel plug assay). E2-2 interacts with Id1 via their HLH domains; Id1 interferes with E2-2-mediated transcriptional repression and rescues E2-2-mediated inhibition of angiogenesis. E2-2 inhibits VEGFR2 expression by suppressing VEGFR2 promoter activity. Adenoviral overexpression in vivo (Matrigel plug), EC migration/network/proliferation assays, mutational analysis of HLH domain, luciferase reporter (VEGFR2 promoter), siRNA knockdown Blood Medium 20231428
2001 TCF4 is present in DNA complexes (with beta-catenin and E-cadherin) that bind the CAAAG Tcf recognition sequence in metastasis-inducing DNA fragments. Transfection of TCF4 expression vector inhibited osteopontin promoter activity stimulated by active Met-DNA fragments, indicating TCF4 acts as an endogenous repressor of osteopontin transcription by binding to CAAAG elements. Electrophoretic mobility shift assay (EMSA), Western blotting of DNA-protein complexes, co-transfection reporter assay, osteopontin mRNA measurement Cancer research Medium 11454716
2001 ITF2/E2-2 suppresses melanogenic gene expression and Mitf transcription factor expression in melanocytes, as demonstrated by overexpression and antisense constructs with luciferase reporter assays and gene/protein expression analyses. Stable ITF2 overexpression reduced pigmentation and dendritic morphology; antisense knockdown enhanced both, establishing ITF2 as a functional repressor of the melanocyte differentiation program. Stable transfection of sense/antisense constructs, luciferase reporter assays with melanogenic gene promoters, gene expression analysis, pigmentation assays The Journal of biological chemistry Medium 11382753
2008 TCF4 occupies 6,868 high-confidence chromatin binding sites genome-wide in the LS174T colorectal cancer cell line. TCF4-binding sites are predominantly distal from transcription start sites, are enriched for evolutionarily conserved A-C/G-A/T-T-C-A-A-A-G motifs, and frequently function as beta-catenin/TCF4-dependent enhancers in reporter assays. Chromatin immunoprecipitation combined with genome-wide DNA array (ChIP-chip), motif discovery, luciferase enhancer reporter assays Molecular and cellular biology High 18268006
2008 Beta-catenin/TCF4 signaling directly upregulates the splicing factor SRp20 transcription. Activated beta-catenin increased endogenous SRp20 and stimulated an SRp20 promoter luciferase reporter, while dominant-negative TCF4 reduced both. Increased SRp20 was sufficient to alter alternative splicing of CD44 and a minigene reporter, demonstrating that the beta-catenin/TCF4 pathway regulates alternative splicing via SRp20. Dominant-negative TCF4 transfection, activated beta-catenin mutants, luciferase reporter assays, RT-PCR splicing assays, minigene reporter RNA Medium 18952824
2012 Pitt-Hopkins syndrome-associated missense mutations in the bHLH domain of TCF4 alter subnuclear localization of the mutant protein and attenuate homo- and heterodimer formation (measured by HTRF). Mutations proximal to the bHLH domain do not alter localization or dimerization. TCF4 transactivates the NRXN1β and CNTNAP2 promoters in luciferase assays; PTHS mutants show variable, context-specific deficits in transactivating these promoters when co-expressed with different bHLH transcription factors. Homogenous time-resolved fluorescence (HTRF) dimerization assays, subnuclear localization imaging, luciferase reporter assays with NRXN1β and CNTNAP2 promoters Human mutation Medium 22777675
2012 Kindlin 2 directly interacts with active beta-catenin and forms a tripartite complex with beta-catenin and TCF4 (confirmed by co-IP). Kindlin 2 selectively strengthens beta-catenin occupancy on the Axin2 promoter and enhances Axin2 gene expression, thereby promoting tumor cell invasion through a beta-catenin–Axin2–Snail cascade. Co-immunoprecipitation, chromatin immunoprecipitation (Axin2 promoter occupancy), reporter assays, invasion assays EMBO reports Medium 22699938
2018 TRIB3 physically interacts with beta-catenin and TCF4 (confirmed by immunoprecipitation). TRIB3 overexpression increased recruitment of TCF4 and beta-catenin to promoters of Wnt target genes; TRIB3 knockdown decreased this recruitment. A peptide (P2-T3A6) that binds beta-catenin disrupted its interaction with TRIB3 and TCF4. Co-immunoprecipitation, chromatin immunoprecipitation, dual luciferase reporter, peptide inhibitor disruption assay, in vivo mouse models Gastroenterology Medium 30365932
2017 TEAD4 associates with TCF4 to form a complex that co-binds target gene loci. VGLL4 targets this TEAD4-TCF4 complex to interfere with TEAD4-TCF4 functional interplay and suppress TCF4 transactivation, directly linking Wnt/beta-catenin and Hippo-YAP signaling at the transcription factor level. Co-immunoprecipitation, ChIP, reporter assays, VGLL4-mimicking peptide, in vivo mouse CRC model Nature communications Medium 28051067
2014 ITF2/TCF4 prevents activation of the beta-catenin-TCF4 complex in colorectal cancer cells by competing with TCF4 for beta-catenin binding, thereby inhibiting expression of Wnt target genes. Stable ITF2 overexpression reduced proliferation and tumorigenic potential in xenograft models; ITF2 knockdown promoted xenograft tumor growth. Co-immunoprecipitation, TOPFLASH luciferase reporter, shRNA knockdown, stable transgenic overexpression, xenograft mouse models Gastroenterology Medium 24846398
2015 TCF3 binds the MYC 3' Wnt-responsive element (WRE) to repress MYC expression. TCF3 depletion increases availability of the WRE for TCF4/beta-catenin complex binding. Inhibiting GSK3β causes an exchange of TCF3 for TCF4/beta-catenin at the MYC 3' WRE to activate MYC, and this TCF3-to-TCF4 switch controls MYC expression as quiescent cells re-enter the cell cycle. ChIP, shRNA-mediated TCF3 depletion, GSK3β inhibition, MYC expression analysis, cell cycle analysis Cell cycle Medium 25659031
2019 The bHLH domain of TCF4 preferentially binds DNA containing 5-carboxylcytosine (5caC) at the flanking CpG of E-box elements. Crystal structures of TCF4 bHLH in complex with unmodified and 5caC-modified oligonucleotides reveal that the basic region adopts multiple conformations; Arg576 can interact with 5caC in the major groove. Five Arg residues in the basic region mutated in Pitt-Hopkins syndrome (including R569 and R576) are directly involved in 5caC recognition. Protein crystallography (crystal structures), in vitro DNA binding assays, mutagenesis of Pitt-Hopkins syndrome-associated residues Nucleic acids research High 31081034
2016 TCF4 is a master regulator of the BPDCN oncogenic transcriptional program; its RNAi-mediated downregulation caused loss of the BPDCN-specific gene expression program and apoptosis. TCF4 controls BPDCN-specific super-enhancers, and BET inhibitors disrupt this TCF4-dependent transcriptional network, inducing apoptosis and retarding xenograft growth. RNAi screening, shRNA knockdown, gene expression profiling, BET inhibitor treatment, xenograft mouse models Cancer cell Medium 27846392
2019 Gains of 18q21.2 targeting the TCF4 gene are the most frequent genetic alteration in ABC-like DLBCL. TCF4 overexpression in ABC-like DLBCL cell lines led to its occupancy on IGHM and MYC gene enhancers and increased expression of IgM and MYC at transcript and protein levels. Dominant-negative TCF4 constructs were synthetically lethal to cell lines harboring TCF4 copy gains. DNA copy number profiling, ChIP (TCF4 occupancy on IGHM and MYC enhancers), overexpression studies, dominant-negative constructs, BET PROTAC treatment, xenograft models Science translational medicine Medium 31217338
2014 Zac1 directly activates the Tcf4 gene in neuronal progenitors by binding two cis-regulatory elements in the Tcf4 locus (shown by ChIP). Tcf4 upregulation enhances expression of the imprinted CDK inhibitor p57(Kip2), a Tcf4 target gene, and increases G1 phase cell number, establishing a Zac1→Tcf4→p57(Kip2) axis controlling cell cycle arrest in neuronal progenitors. ChIP identifying Zac1 binding at Tcf4 locus, luciferase reporter assays for cis-regulatory elements, Tcf4 overexpression, cell cycle analysis Molecular and cellular biology Medium 24396065
2020 Tcf4 loss-of-function in mice causes mis-specification of cortical neurons, malformation of the corpus callosum and anterior commissure, hippocampal hypoplasia, and loss of GFAP-expressing midline glia. RNA-sequencing of E14.5 cortex shows Tcf4 functions as a transcriptional activator; its deletion downregulates genes linked to neurogenesis and neuronal maturation. Conditional knockout mice, immunohistochemistry, RNA-sequencing, morphological analysis Molecular and cellular neurosciences Medium 32474139
2021 TCF4 and SOX11 biochemically interact (confirmed by co-IP) and cooperatively control commissure formation in vivo. scRNA-seq regulon analysis indicates TCF4 modulates activity of non-bHLH transcription factors (including FOXG1, SOX11, BRG1) in cortical projection neurons, and TCF4/SOX11 cooperatively regulate transcription of genes implicated in commissure formation. Single-cell RNA-sequencing, TF regulon analysis, co-immunoprecipitation, in vivo commissure formation assay Development Medium 34184026
2009 TCF4 mutations in the basic domain of the bHLH domain impair heterodimerization with tissue-specific transcription factors less effectively than homodimerization in luciferase reporter assays, and the basic domain is a mutational hotspot in Pitt-Hopkins syndrome patients. Luciferase reporter assays, mutational analysis, patient cohort analysis Human mutation Medium 19235238
2016 Tcf4 haploinsufficient mice show enhanced long-term potentiation in CA1 hippocampus. HDAC inhibitors normalized hippocampal LTP and memory recall in Tcf4+/- mice. Hdac2 isoform-selective knockdown was sufficient to rescue memory deficits, establishing that TCF4 haploinsufficiency acts partly through an HDAC2-dependent epigenetic mechanism to impair memory. Tcf4+/- mouse model, electrophysiology (LTP), behavioral assays, HDAC inhibitor treatment, antisense oligonucleotide Hdac2 knockdown, next-generation sequencing of hippocampal mRNA and methylated DNA Cell reports Medium 27568567
2021 Acute cell-specific deletion of Tcf4 in adult excitatory neurons in vivo caused hyperexcitability and increased dendritic complexity, distinct from effects of embryonic deficiency. Transcriptomic analysis of adult-deleted neurons revealed Tcf4 targets in adult neurons are distinct from embryonic targets, with plasma membrane and ciliary genes specifically underlying adult neuron structure-function regulation. Adult conditional (Cre-lox) neuron-specific KO, electrophysiology, dendritic morphology analysis, FACS-sorted neuron transcriptomics Translational psychiatry Medium 34564703
2022 Postnatal reinstatement of Tcf4 expression in neurons of a conditional Tcf4 mouse model of Pitt-Hopkins syndrome improved anxiety-like behavior, activity levels, innate behaviors, memory, partially corrected EEG abnormalities, and normalized expression of key TCF4-regulated genes, supporting that TCF4 haploinsufficiency is reversible postnatally by gene normalization. Conditional Tcf4 mouse model, viral gene therapy (postnatal Tcf4 reinstatement), behavioral assays, EEG recording, gene expression analysis eLife Medium 35535852
2011 Connective tissue fibroblasts regulate muscle fiber type development and maturation via Tcf4-dependent signals; fibroblasts promote slow myogenesis by stimulating slow myosin heavy chain expression (Tcf4-dependent) and suppress fetal-to-adult muscle switching by repressing embryonic myosin (Tcf4-dependent). Low levels of Tcf4 intrinsically in myogenic cells also promote both slow and fast myogenesis, revealing a novel intrinsic mechanism. Tcf4GFPCre genetic manipulation of connective tissue fibroblasts, fiber type analysis, Tcf4 conditional KO, slow/fast myosin heavy chain expression analysis Development Medium 21177349
2007 TCF4 expressed in the ventral diencephalon negatively regulates pituitary growth by restricting BMP and FGF signaling domains. TCF4-deficient mice show expanded Fgf10/Bmp4 expression domains rostrally, expanded Six6 in Rathke's pouch, and greatly enlarged anterior pituitary, indicating TCF4 restricts pituitary progenitor induction both extrinsically (via BMP/FGF) and intrinsically (via Six6). Tcf4 KO mice, in situ hybridization, immunohistochemistry of signaling molecule expression domains Developmental biology Medium 17919533
2020 The intronic CTG18.1 trinucleotide repeat expansion in TCF4 causes formation of toxic CUG-containing nuclear RNA foci in corneal endothelial cells, sequesters splicing factors, and impairs splicing. Antisense oligonucleotides targeting the mutant CUG repeat RNA potently inhibited RNA foci in patient-derived cells and reversed pathological splicing changes in ex vivo human FECD corneas. Fluorescence in situ hybridization (FISH) for nuclear foci, splicing analysis, antisense oligonucleotide (ASO) treatment of patient cells and ex vivo corneas Human molecular genetics Medium 29325021
2015 Expansion of the intronic CTG18.1 triplet repeat locus in TCF4 produces nuclear RNA foci containing expanded CUG transcripts in corneal endothelial samples from FECD patients with the expansion (foci in 33–88% of cells), but not in controls lacking the expansion, implicating toxic RNA as a mechanism in FECD pathogenesis. TCF4 constitutive exon expression was unaltered, suggesting haploinsufficiency is not the primary mechanism. Fluorescence in situ hybridization (FISH) for RNA foci, quantitative RT-PCR of TCF4 expression Investigative ophthalmology & visual science Medium 25722209
2020 UHRF2 directly interacts with and sumoylates Tcf4 (confirmed by co-IP), stabilizing Tcf4 protein and sustaining hyperactive Wnt/beta-catenin signaling in intestinal tumors. Uhrf2-null ApcMin mice showed strongly reduced tumor initiation, and Uhrf2 loss suppressed Wnt/beta-catenin pathway activity, establishing a SUMOylation-dependent feedforward loop between Uhrf2 and Tcf4. Co-immunoprecipitation, sumoylation assays, conditional KO mice (Uhrf2 null on ApcMin background), organoid formation, Wnt reporter assays International journal of cancer Medium 32372448
2009 HINT1 overexpression in hepatoma cells inhibits beta-catenin/TCF4 transcriptional activity and cyclin D1 expression. HINT1 co-immunoprecipitates with USF2, suggesting a physical interaction, while NFkappaB p65 nuclear translocation is also inhibited, establishing HINT1 as a repressor of the beta-catenin/TCF4 axis in hepatoma cells. Luciferase reporter assay (TCF4 reporter), co-immunoprecipitation, Western blot, nuclear fractionation International journal of cancer Low 19089909
2006 E2-2/TCF4 is required for optimal expansion of pro-B cells; E2-2-deficient fetal liver cells showed reduced frequency of responding B cell progenitors at the pro-B stage. E2-2 deficiency also skewed peripheral B cell repertoire toward marginal zone (MZ) at the expense of follicular B cells, indicating E2-2 influences the follicular versus MZ B cell fate decision. Fetal liver cell transfer into irradiated Rag-deficient mice, stromal cell/IL-7 culture, real-time PCR of E-protein expression, flow cytometry of B cell subsets Journal of immunology Medium 17082585
2008 E2-2/TCF4 is expressed during DN stages of thymocyte development and E2-2-null thymocytes display a partial block at the DN3 stage with reduced pre-Tα expression, a gene known to be regulated by E2A and HEB, indicating E2-2 operates cooperatively with E2A and HEB during early T cell development. E2-2 KO mouse analysis, flow cytometry of thymocyte populations, RT-PCR of E-protein and pre-Tα expression Molecular immunology Medium 18384878
2019 Combined disruption of E2-2 and HEB in mice results in failure to express the early lymphoid program in common lymphoid precursors (CLPs) and near-complete block of B-cell development; ETPs were reduced and T-cell development perturbed. HSCs, erythro-myeloid progenitors, and innate immune cells were unaffected, demonstrating E2-2 and HEB are specifically required for lymphoid lineage specification. Double conditional KO mice (E2-2 and HEB), flow cytometry of progenitor and mature immune cell populations, adoptive transfer Frontiers in immunology Medium 30936870
2019 TCF4 serves as a master regulator of the mesenchymal-like (MES) transcriptional program in melanoma, suppressing melanocytic and antigen presentation programs. Targeting TCF4 genetically or pharmacologically with a bromodomain inhibitor increased immunogenicity and sensitivity of MES cells to immune checkpoint blockade and targeted therapy. Single-cell multi-omics, genetic TCF4 knockdown, BRD inhibitor treatment, functional immunogenicity assays Cell Medium 38181739
2011 TCF4 functions in macrophage lineage specification downstream of GM-CSF receptor signaling: forced expression of Tcf4 or stabilized beta-catenin is sufficient to promote macrophage differentiation in response to GM-CSF. GM-CSF regulates beta-catenin stability most likely via GSK3β, and GSK3β inhibition promotes macrophage over granulocyte colony formation from primary cells. Retroviral Tcf4 overexpression, stabilized beta-catenin expression, Wnt target gene reporter assays, GSK3β inhibition, primary colony assays Differentiation Medium 22099176
2023 NF-κB p65 stabilizes ITF2/TCF4 protein by binding to its N-terminus and blocking Parkin-mediated ubiquitination of ITF2. Parkin acts as the E3 ubiquitin ligase for ITF2 ubiquitination. Intestinal epithelial-specific deletion of ITF2 enhanced nuclear p65 translocation and increased colitis-associated cancer tumorigenesis. Co-immunoprecipitation (p65–ITF2 interaction), ubiquitination assays, conditional intestinal epithelial KO, AOM/DSS cancer model, protein stability assays Nature communications High 37185280
2018 CHAF1A directly interacts with TCF4 (confirmed by co-immunoprecipitation) and acts as a co-activator in the Wnt pathway. The CHAF1A-TCF4 complex binds promoter regions of c-MYC and CCND1, enhancing their expression and promoting gastric cancer cell proliferation. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP at c-MYC and CCND1 promoters), overexpression and knockdown, luciferase reporter, in vivo xenograft EBioMedicine Medium 30449701
2025 TCF4 controls the development of the DC2A (CD7+CD11blo) lineage of conventional dendritic cells in a TCF4-dependent manner from Siglec-H+CD115- pre-DC2 progenitors, as shown by conditional knockout and fate-mapping. Single-cell sequencing, conditional TCF4 knockout mice, fate-mapping, adoptive transfer Nature immunology Medium 40702338

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 536 18854153
1992 HEB, a helix-loop-helix protein related to E2A and ITF2 that can modulate the DNA-binding ability of myogenic regulatory factors. Molecular and cellular biology 283 1312219
2011 Connective tissue fibroblasts and Tcf4 regulate myogenesis. Development (Cambridge, England) 249 21177349
2010 E2-2 protein and Fuchs's corneal dystrophy. The New England journal of medicine 231 20825314
2010 Continuous expression of the transcription factor e2-2 maintains the cell fate of mature plasmacytoid dendritic cells. Immunity 220 21145760
2008 Genome-wide pattern of TCF7L2/TCF4 chromatin occupancy in colorectal cancer cells. Molecular and cellular biology 194 18268006
2011 Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Human molecular genetics 165 21791550
2024 A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma. Cell 148 38181739
2018 TRIB3 Interacts With β-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis. Gastroenterology 143 30365932
1993 E2A and E2-2 are subunits of B-cell-specific E2-box DNA-binding proteins. Molecular and cellular biology 143 8497267
2003 Sumoylation is involved in beta-catenin-dependent activation of Tcf-4. The EMBO journal 142 12727872
2017 VGLL4 targets a TCF4-TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer. Nature communications 133 28051067
2016 A Druggable TCF4- and BRD4-Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm. Cancer cell 133 27846392
2014 The emerging roles of TCF4 in disease and development. Trends in molecular medicine 133 24594265
1999 Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium. The American journal of pathology 131 9916915
2009 Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. Human mutation 127 19235238
2016 Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function. Cell reports 114 27568567
2020 TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease. Progress in retinal and eye research 102 32735996
2012 Kindlin 2 forms a transcriptional complex with β-catenin and TCF4 to enhance Wnt signalling. EMBO reports 96 22699938
2015 TCF4 Triplet Repeat Expansion and Nuclear RNA Foci in Fuchs' Endothelial Corneal Dystrophy. Investigative ophthalmology & visual science 93 25722209
2013 Pitt-Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription. Experimental & molecular medicine 92 23640545
2016 Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification. Immunity 87 27986456
2007 TCF4 deficiency expands ventral diencephalon signaling and increases induction of pituitary progenitors. Developmental biology 84 17919533
2011 Differential LEF1 and TCF4 expression is involved in melanoma cell phenotype switching. Pigment cell & melanoma research 80 21599871
2019 Dual Expression of TCF4 and CD123 Is Highly Sensitive and Specific For Blastic Plasmacytoid Dendritic Cell Neoplasm. The American journal of surgical pathology 74 31261288
2017 Discovery of small molecule inhibitors of the Wnt/β-catenin signaling pathway by targeting β-catenin/Tcf4 interactions. Experimental biology and medicine (Maywood, N.J.) 72 28474989
2019 Disruption of TCF4 regulatory networks leads to abnormal cortical development and mental disabilities. Molecular psychiatry 71 30705426
2023 Oridonin promotes endoplasmic reticulum stress via TP53-repressed TCF4 transactivation in colorectal cancer. Journal of experimental & clinical cancer research : CR 70 37337284
2021 TCF4 enhances hepatic metastasis of colorectal cancer by regulating tumor-associated macrophage via CCL2/CCR2 signaling. Cell death & disease 68 34580284
2018 Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy. Human molecular genetics 61 29325021
2010 TCF4, schizophrenia, and Pitt-Hopkins Syndrome. Schizophrenia bulletin 60 20421335
2019 Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma. Science translational medicine 59 31217338
2012 Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome. Human mutation 58 22777675
2008 The beta-catenin/TCF4 pathway modifies alternative splicing through modulation of SRp20 expression. RNA (New York, N.Y.) 58 18952824
2000 HASH-1 and E2-2 are expressed in human neuroblastoma cells and form a functional complex. Biochemical and biophysical research communications 57 10903890
2008 TCF4 deletions in Pitt-Hopkins Syndrome. Human mutation 55 18781613
2001 Metastasis-inducing dna regulates the expression of the osteopontin gene by binding the transcription factor Tcf-4. Cancer research 55 11454716
2019 Knockdown of lncRNA MFI2-AS1 inhibits lipopolysaccharide-induced osteoarthritis progression by miR-130a-3p/TCF4. Life sciences 54 31678554
2019 Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia. Science advances 53 31535015
2014 Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective. Cellular and molecular life sciences : CMLS 50 24413739
2010 LEF-1 and TCF4 expression correlate inversely with survival in colorectal cancer. Journal of translational medicine 50 21092222
2018 miR-137 suppresses proliferation, migration and invasion of colon cancer cell lines by targeting TCF4. Oncology letters 47 29805612
2020 Tcf4 is required for correct brain development during embryogenesis. Molecular and cellular neurosciences 44 32474139
2016 SPOP promotes tumor progression via activation of β-catenin/TCF4 complex in clear cell renal cell carcinoma. International journal of oncology 42 27572476
2015 A dynamic exchange of TCF3 and TCF4 transcription factors controls MYC expression in colorectal cancer cells. Cell cycle (Georgetown, Tex.) 42 25659031
2012 TCF4 (e2-2; ITF2): a schizophrenia-associated gene with pleiotropic effects on human disease. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 41 23129290
2010 Colorectal tumors are effectively eradicated by combined inhibition of {beta}-catenin, KRAS, and the oncogenic transcription factor ITF2. Cancer research 41 20823162
2014 Zac1 regulates cell cycle arrest in neuronal progenitors via Tcf4. Molecular and cellular biology 40 24396065
2009 MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated epithelial-mesenchymal transdifferentiation. The Journal of biological chemistry 40 19443654
2001 Involvement of ITF2 in the transcriptional regulation of melanogenic genes. The Journal of biological chemistry 40 11382753
2002 Expression and splice variant analysis of the zebrafish tcf4 transcription factor. Mechanisms of development 39 12204269
2019 β-Catenin/TCF4 Complex-Mediated Induction of the NRF3 (NFE2L3) Gene in Cancer Cells. International journal of molecular sciences 38 31288376
2009 HINT1 inhibits beta-catenin/TCF4, USF2 and NFkappaB activity in human hepatoma cells. International journal of cancer 38 19089909
2006 Physiological and functional interactions between Tcf4 and Daxx in colon cancer cells. The Journal of biological chemistry 35 16569639
2010 Inhibition of endothelial cell activation by bHLH protein E2-2 and its impairment of angiogenesis. Blood 33 20231428
2020 Region and Cell Type Distribution of TCF4 in the Postnatal Mouse Brain. Frontiers in neuroanatomy 31 32765228
2004 Aberrant expression and function of TCF4 in the proliferation of hepatocellular carcinoma cell line BEL-7402. Cell research 31 15040893
2021 TCF4 and HuR mediated-METTL14 suppresses dissemination of colorectal cancer via N6-methyladenosine-dependent silencing of ARRDC4. Cell death & disease 30 34916487
2018 CHAF1A interacts with TCF4 to promote gastric carcinogenesis via upregulation of c-MYC and CCND1 expression. EBioMedicine 30 30449701
2023 MACF1 overexpression in BMSCs alleviates senile osteoporosis in mice through TCF4/miR-335-5p signaling pathway. Journal of orthopaedic translation 29 36969134
2020 miR-129-5p Inhibits Bone Formation Through TCF4. Frontiers in cell and developmental biology 28 33240893
2016 Regulation of Melanoma Progression through the TCF4/miR-125b/NEDD9 Cascade. The Journal of investigative dermatology 28 26968260
2020 Circ-TCF4.85 silencing inhibits cancer progression through microRNA-486-5p-targeted inhibition of ABCF2 in hepatocellular carcinoma. Molecular oncology 27 31758671
2019 Structural basis for preferential binding of human TCF4 to DNA containing 5-carboxylcytosine. Nucleic acids research 27 31081034
2019 TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer. PloS one 27 31536510
2014 ITF2 prevents activation of the β-catenin-TCF4 complex in colon cancer cells and levels decrease with tumor progression. Gastroenterology 27 24846398
1999 Analysis of genome-wide CAG/CTG repeats, and at SEF2-1B and ERDA1 in schizophrenia and bipolar affective disorder. Molecular psychiatry 27 10395212
2017 WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene . Molecular neuropsychiatry 26 28879201
2015 Wnt1 positively regulates CD36 expression via TCF4 and PPAR-γ in macrophages. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 26 25721714
2020 UHRF2 promotes intestinal tumorigenesis through stabilization of TCF4 mediated Wnt/β-catenin signaling. International journal of cancer 25 32372448
2017 The importance of TCF4 gene in the etiology of recurrent depressive disorders. Progress in neuro-psychopharmacology & biological psychiatry 25 28341444
2022 Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression. eLife 24 35535852
2018 Tcf4 regulates dendritic spine density and morphology in the adult brain. PloS one 24 29933371
2016 Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability. Orphanet journal of rare diseases 24 27179618
2011 The GM-CSF receptor utilizes β-catenin and Tcf4 to specify macrophage lineage differentiation. Differentiation; research in biological diversity 24 22099176
2021 Covalent and Noncovalent Targeting of the Tcf4/β-Catenin Strand Interface with β-Hairpin Mimics. ACS chemical biology 23 34286954
2020 TCF4 promotes colorectal cancer drug resistance and stemness via regulating ZEB1/ZEB2 expression. Protoplasma 23 31933004
2025 Transcription factors TCF4 and KLF4 respectively control the development of the DC2A and DC2B lineages. Nature immunology 21 40702338
2021 miR-133a-5p suppresses gastric cancer through TCF4 down-regulation. Journal of gastrointestinal oncology 21 34295552
2019 TCF4 (E2-2) harbors tumor suppressive functions in SHH medulloblastoma. Acta neuropathologica 21 30830316
2019 miR-139-5p reverses stemness maintenance and metastasis of colon cancer stem-like cells by targeting E2-2. Journal of cellular physiology 21 31120140
2006 E2-2 regulates the expansion of pro-B cells and follicular versus marginal zone decisions. Journal of immunology (Baltimore, Md. : 1950) 20 17082585
2020 Long Noncoding RNA PTPRG Antisense RNA 1 Reduces Radiosensitivity of Nonsmall Cell Lung Cancer Cells Via Regulating MiR-200c-3p/TCF4. Technology in cancer research & treatment 19 33174523
2011 Impact of TCF4 on the genetics of schizophrenia. European archives of psychiatry and clinical neuroscience 19 21932083
2019 Expression and clinical significance of transcription factor 4 (TCF4) in epithelial ovarian cancer. Cancer biomarkers : section A of Disease markers 18 30614797
2019 The Concerted Action of E2-2 and HEB Is Critical for Early Lymphoid Specification. Frontiers in immunology 18 30936870
2015 Characterization of species-specific genes regulated by E2-2 in human plasmacytoid dendritic cells. Scientific reports 18 26182859
2015 TCF4 gene polymorphism is associated with cognition in patients with schizophrenia and healthy controls. Journal of psychiatric research 18 26343600
2008 Clinicopathological significance of expression of p-c-Jun, TCF4 and beta-Catenin in colorectal tumors. BMC cancer 18 18992165
2023 β-catenin/TCF4 inhibitors ICG-001 and LF3 alleviate BDL-induced liver fibrosis by suppressing LECT2 signaling. Chemico-biological interactions 17 36639009
2021 scRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse. Development (Cambridge, England) 17 34184026
2024 Deciphering novel TCF4-driven mechanisms underlying a common triplet repeat expansion-mediated disease. PLoS genetics 16 38713708
2024 TCF4 trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy. Redox biology 16 39332053
2021 Increased miR-6875-5p inhibits plasmacytoid dendritic cell differentiation via the STAT3/E2-2 pathway in recurrent spontaneous abortion. Molecular human reproduction 16 34240166
2021 Adult brain neurons require continual expression of the schizophrenia-risk gene Tcf4 for structural and functional integrity. Translational psychiatry 16 34564703
2019 Targeting transcription factor TCF4 by γ-Mangostin, a natural xanthone. Oncotarget 16 31608135
2024 Suppression of TCF4 promotes a ZC3H12A-mediated self-sustaining inflammatory feedback cycle involving IL-17RA/IL-17RE epidermal signaling. JCI insight 15 38470486
2024 Tissue-specific TCF4 triplet repeat instability revealed by optical genome mapping. EBioMedicine 15 39278108
2023 Protein stabilization of ITF2 by NF-κB prevents colitis-associated cancer development. Nature communications 15 37185280
2008 A role for E2-2 at the DN3 stage of early thymopoiesis. Molecular immunology 15 18384878

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