Affinage

TCF7

Transcription factor 7 · UniProt P36402

Length
384 aa
Mass
41.6 kDa
Annotated
2026-04-28
100 papers in source corpus 46 papers cited in narrative 45 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TCF-1 (encoded by TCF7) is a sequence-specific HMG-box transcription factor that serves as a master regulator of T cell and innate lymphoid cell (ILC) lineage identity, chromatin architecture, and stem-like T cell maintenance. TCF-1 binds the minor groove of DNA at AACAAAG motifs in T cell receptor and other lymphoid gene enhancers, activating or repressing transcription through both β-catenin-dependent and -independent mechanisms; its N-terminal β-catenin-binding domain is required for thymocyte survival via Bcl-xL induction and for CD8+ memory T cell generation (PMID:1989880, PMID:11477404, PMID:20457902). As a pioneer-like factor, TCF-1 displaces nucleosomes to establish de novo chromatin accessibility at T cell-restricted loci, co-occupies genomic sites with CTCF to reorganize three-dimensional genome topology, and epigenetically silences alternative lineage programs including IL-17/RORγt, MAF, and LEF-1, whose aberrant upregulation in TCF-1-deficient mice causes T-ALL (PMID:29466756, PMID:35726060, PMID:23103132, PMID:31142588). TCF-1 also sustains stem-like TCF-1⁺ precursor exhausted CD8⁺ T cells during chronic infection and cancer—maintained by TGF-β, IL-33–ST2, and IL-10R–STAT3 signals—and initiates T follicular helper differentiation by directly activating Bcl6 and repressing Blimp1 (PMID:31606264, PMID:36809763, PMID:26214740).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1991 High

    The identity of the T cell-specific factor recognizing TCR/CD3 enhancers was unknown; cloning and biochemical characterization of TCF-1 revealed a single HMG-box protein that binds AACAAAG motifs and transactivates in T cells, establishing TCF-1 as the founding TCR enhancer-binding factor.

    Evidence Protein purification, gel retardation, methylation interference, cotransfection reporter assays, cDNA cloning in human and murine T cells

    PMID:1827138 PMID:1836958 PMID:1989880

    Open questions at the time
    • Three-dimensional structure of TCF-1 HMG box on DNA not yet determined
    • Mechanism of T cell-specific expression not defined
  2. 1992 High

    How TCF-1/HMG-box proteins contact DNA was unclear; footprinting showed recognition occurs predominantly through minor groove contacts without major groove guanine interactions, distinguishing this from classical transcription factor binding modes.

    Evidence Methylation interference, DEPC carbethoxylation, nucleotide substitution assays

    PMID:1639073

    Open questions at the time
    • Structural basis for sequence selectivity via minor groove not resolved at atomic level
  3. 1993 High

    Whether TCF-1 has an autonomous activation domain was unresolved; mapping identified a bipartite, context-dependent activation domain (aa 80–256) that functions only with cooperating elements, and alternative promoter usage was shown to generate functionally distinct long and short isoforms.

    Evidence GAL4 fusion mutagenesis, reporter assays in T cell lines, cDNA cloning and RACE

    PMID:8253387 PMID:8622675

    Open questions at the time
    • Cofactors mediating context-dependent activation not identified
    • Relative isoform abundance across developmental stages incompletely mapped
  4. 2001 High

    The functional requirement for β-catenin interaction was unknown; domain-specific knock-in mice demonstrated that the β-catenin-binding domain is essential for DP thymocyte survival via Bcl-xL, and that Wnt1/Wnt4 ligands activate TCF-1-dependent transcription in thymocytes.

    Evidence β-catenin-binding domain deletion knock-in mice, Bcl-2 transgene rescue, Tcf-LacZ reporter mice, retroviral Wnt blockade

    PMID:11265645 PMID:11477404

    Open questions at the time
    • Whether γ-catenin compensates in vivo not tested
    • Upstream Wnt ligand source in thymic microenvironment not defined
  5. 2010 High

    Whether TCF-1 functions in CD8+ memory formation was untested; knockout and domain-mutant studies showed TCF-1's β-catenin-binding domain is required for central memory CD8+ T cell generation, with β-catenin and γ-catenin as coactivators.

    Evidence Tcf-1 KO mice, LCMV infection, secondary challenge, catenin-binding domain mutant analysis

    PMID:20457902

    Open questions at the time
    • Direct TCF-1 target genes in memory precursors not identified
    • Relative contribution of β- vs. γ-catenin not dissected
  6. 2011 High

    Whether TCF-1 is sufficient to initiate T cell fate was unknown; forced TCF-1 expression in bone marrow progenitors drove T lineage gene programs (Gata3, Bcl11b) even without Notch, placing TCF-1 downstream of Notch as a T cell fate-determining factor, while also revealing epigenetic repression of IL-17 loci.

    Evidence Retroviral gain-of-function in BM progenitors, in vivo development assays, ChIP for histone modifications at IL-17 locus in KO mice

    PMID:21814277 PMID:21935461

    Open questions at the time
    • Whether TCF-1 alone is sufficient without any other Notch-induced factors unclear
    • Mechanism of epigenetic silencing (writer/eraser recruitment) not identified
  7. 2012 High

    How TCF-1 loss causes T-ALL was unexplained; ChIP and genetic epistasis demonstrated TCF-1 directly represses LEF-1 transcription, and aberrant LEF-1 upregulation drives T cell malignancy, which is rescued by conditional Lef1 deletion.

    Evidence ChIP at Lef1 locus, Tcf7 KO mice developing T-ALL, conditional Lef1 KO rescue

    PMID:23103132

    Open questions at the time
    • Whether LEF-1 is the sole oncogenic driver or cooperates with other derepressed genes not fully resolved
  8. 2014 High

    How TCF-1 controls CD4/CD8 lineage choice was mechanistically unclear; TCF-1 was shown to directly activate ThPOK for CD4 fate and physically interact with Runx3 to silence Cd4 in CD8 cells, revealing dual mechanisms for lineage bifurcation.

    Evidence DP-specific conditional KO, ChIP, Co-IP for TCF-1–Runx3 interaction, reporter assays

    PMID:24836425

    Open questions at the time
    • Whether the TCF-1–Runx3 interaction is direct or bridged by other factors not resolved by Co-IP alone
  9. 2015 High

    TCF-1's role in T follicular helper differentiation was unknown; ChIP demonstrated direct TCF-1 binding at Bcl6 and Prdm1 loci to activate Bcl-6 and repress Blimp1, while also sustaining IL-6Rα/gp130 and ICOS expression, positioning TCF-1 as the initiator of the TFH program. Concurrently, TCF-1 was established as essential for all ILC subsets by marking early ILC-committed progenitors.

    Evidence ChIP at Bcl6/Prdm1 loci, Tcf7 KO with LCMV infection, Tcf7 reporter mice for ILC progenitor identification, conditional KO lineage assays

    PMID:26214740 PMID:26214741 PMID:26280998

    Open questions at the time
    • Whether TCF-1 directly or indirectly regulates Bcl6 in TFH vs. GC-B cells not distinguished
    • Cofactors at ILC progenitor stage not defined
  10. 2018 High

    Whether TCF-1 functions as a pioneer factor to establish chromatin accessibility was untested; ATAC-seq across developmental stages and gain-of-function in fibroblasts showed TCF-1 opens chromatin de novo at T cell-restricted loci, displaces nucleosomes, and protects HEB from Notch-mediated degradation at co-occupied sites.

    Evidence ATAC-seq, ChIP-seq, TCF-1 ectopic expression in fibroblasts, proteasome inhibition assays, conditional KO

    PMID:29466756 PMID:30420627

    Open questions at the time
    • Whether TCF-1 directly contacts and displaces histones or requires remodeling machinery not determined
    • Genome-wide nucleosome displacement kinetics not measured
  11. 2019 High

    How TCF-1 governs the bifurcation between terminal effector and exhausted precursor CD8+ T cells was unclear; scRNA-seq and lineage tracing revealed TCF-1 represses terminal effector fate, promotes Eomes and c-Myb for survival, and limits Tc17 development by sequentially suppressing MAF and RORγt. In ILCs, TCF-1 binds pre-existing regulatory elements to enforce lineage commitment while restricting DC potential.

    Evidence scRNA-seq, lineage tracing, TCF-1 conditional KO in chronic LCMV and DP thymocytes, ATAC-seq, adoptive transfer

    PMID:31142588 PMID:31358996 PMID:31606264

    Open questions at the time
    • Direct TCF-1 target genes maintaining the exhausted precursor state not comprehensively defined
    • Whether MAF/RORγt suppression is via direct promoter binding or indirect chromatin remodeling not fully resolved
  12. 2021 Medium

    The cytokine signals and chromatin mechanisms sustaining TCF-1+ stem-like CD8+ T cells were incompletely understood; multiple studies revealed IL-10R–STAT3 maintains the TCF-1+ pool by preserving NFAT/AP-1 cooperativity, Regnase-1 post-transcriptionally limits Tcf7 mRNA abundance, and TCF-1 suppresses alternative TH17 programs at Foxp3 co-bound genes in Tregs.

    Evidence Il10rb/Stat3 conditional KO with ATAC-seq, Regnase-1 KO with CAR-T functional assays, Treg-specific TCF-1 KO with scRNA-seq and ChIP-seq

    PMID:33690816 PMID:34385712 PMID:34879221

    Open questions at the time
    • Whether IL-10R–STAT3 acts directly on Tcf7 transcription or indirectly through chromatin remodeling not resolved
    • Regnase-1 binding site on Tcf7 mRNA not mapped precisely
  13. 2022 High

    How TCF-1 reorganizes 3D genome architecture was unknown; Hi-C revealed TCF-1 co-occupancy with CTCF alters TAD boundaries, creating long-range enhancer-gene contacts with NIPBL recruitment and H3K27ac deposition, while single-cell CRISPR showed TCF-1 acts before T lineage commitment in a kinetic competition with progenitor factors Spi1/Bcl11a.

    Evidence Hi-C, ChIP-seq, ATAC-seq, gain/loss-of-function in T cell progenitors; single-cell CRISPR disruption with scRNA-seq

    PMID:35594339 PMID:35726060

    Open questions at the time
    • Whether TCF-1 directly recruits NIPBL/cohesin or this is an indirect consequence of chromatin opening
    • Relative timing of TCF-1 vs. CTCF binding at remodeled TADs not established
  14. 2023 Medium

    Whether specific cytokine signals maintain TCF-1+ stem-like cells in chronic infection remained incompletely mapped; IL-33–ST2 signaling was shown to be pivotal for expansion of stem-like TCF-1+ CD8+ T cells, with ST2 deficiency causing premature TCF-1 loss rescued by type I IFN blockade, and TGF-β was shown to maintain quiescence of TCF-1+ cells.

    Evidence ST2-KO mice with chronic LCMV, ATAC-seq, IFN blockade rescue; TGF-β receptor conditional KO with transcriptomics

    PMID:35980386 PMID:36809763

    Open questions at the time
    • Whether IL-33 directly induces Tcf7 transcription or acts through chromatin remodeling intermediates
    • Integration of IL-33, TGF-β, and IL-10R signals at the single-cell level not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the structural basis for TCF-1's pioneer-like chromatin remodeling activity, the complete set of direct transcriptional targets maintaining stem-like CD8+ T cells and ILC progenitors, how multiple cytokine inputs (IL-33, TGF-β, IL-10R) are integrated to regulate Tcf7 expression and TCF-1+ cell fate, and whether TCF-1's 3D genome reorganization via CTCF involves direct cohesin recruitment.
  • No structural model of TCF-1 in complex with nucleosomal DNA
  • Comprehensive direct target gene catalog in stem-like T cells lacking
  • Signal integration logic at Tcf7 regulatory elements not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-4839726 Chromatin organization 4
Partners
CTCFCTNNB1FOXP3HEBLEF1RUNX3UCH37
Complex memberships
β-catenin–TCF-1 transcriptional complex

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 TCF-1 was identified as a T cell-specific transcription factor containing a single DNA-binding HMG box that binds to a sequence-specific motif (AACAAAG/TTCAAAG) in the CD3-epsilon and TCR alpha enhancers, and upon cotransfection into non-T cells can transactivate through its cognate motif. Protein purification, gel retardation, methylation interference, cotransfection reporter assays, cDNA cloning The EMBO journal High 1827138 1989880
1992 The HMG boxes of TCF-1 and SRY recognize the heptamer motif A/T A/T C A A A G predominantly through nucleotide contacts in the minor groove of the DNA double helix, without major groove guanine contacts. Methylation interference footprinting, DEPC carbethoxylation interference, T→C and A→I substitution assays The EMBO journal High 1639073
1991 TCF-1 binds specifically to functional T cell-specific elements in the TCR beta (T beta 5) and TCR delta (T delta 7) enhancers, in addition to the CD3-epsilon and TCR alpha enhancers, defining a consensus binding motif A/T A/T C A A/G A G. Gel retardation analysis, sequence comparison International immunology Medium 1836958
1993 TCF-1 (hLEF/TCF-1 alpha) contains a context-dependent transcriptional activation domain (amino acids 80–256, bipartite, proline-rich with tyrosine/serine motifs) separate from the HMG box that activates the TCR alpha enhancer in a T cell- and context-specific manner dependent on the neighboring TCF-2 binding site. GAL4 fusion transactivation assays, deletion and clustered amino acid substitution mutagenesis, reporter gene assays in T cell lines Genes & development High 8253387
1996 TCF-1 is generated from two promoters and extensive alternative splicing producing isoforms of 25–55 kDa; inclusion of an extended N-terminal 116 amino acids (from an upstream promoter) confers similarity to LEF-1 and enables transactivation through the TCR alpha enhancer, establishing functional differences between isoforms. Western blotting, cDNA cloning, RACE, reporter transactivation assays Molecular and cellular biology High 8622675
1999 TCF-1 interacts with beta-catenin to become transcriptionally active in T cells, but unlike fibroblasts, inhibition of GSK-3beta (by lithium or PHA) is insufficient to activate TCF-dependent transcription in T lymphocytes, indicating a cell-type-specific difference in Wnt pathway regulation. Tcf reporter gene assays, dominant-negative GSK-3beta expression, lithium treatment in T cell lines vs. fibroblasts International immunology Medium 10221643
1999 TCF-1 binds to two sites in the Ly49A NK cell receptor promoter and regulates its transcriptional activity; TCF-1 dosage determines the size of the Ly49A NK cell subset in vivo, establishing TCF-1 as a trans-acting regulator of clonal NK receptor acquisition. Promoter binding assays, in vivo TCF-1 dosage analysis in knockout mice Immunity Medium 10549625
2001 The beta-catenin-binding domain of TCF-1 is required for survival of CD4+CD8+ double-positive thymocytes; loss of this domain leads to accelerated apoptosis correlated with decreased Bcl-xL expression, and this survival defect is rescued by a Bcl-2 transgene. Domain deletion knock-in mice, Bcl-2 transgene rescue, apoptosis assays, Bcl-xL expression analysis Nature immunology High 11477404
2001 Wnt1 and Wnt4 signals activate TCF-1-dependent transcription in thymocytes (demonstrated by Tcf-LacZ reporter mice); retroviral expression of soluble Wnt receptor mutants blocking Wnt signaling inhibits thymocyte development, and the beta-catenin–TCF-1 interaction is required for full thymocyte development. Tcf-LacZ reporter mice, retroviral Wnt receptor blockade, in vitro thymocyte culture European journal of immunology Medium 11265645
2005 TCF-1 ensures survival of pre-TCR+ thymocytes through its N-terminal beta-catenin-binding domain; pre-TCR signaling induces TCF-1 expression and activates a Wnt/catenin/TCF reporter, while Wnt signals provide beta-catenin as coactivator, indicating cooperative integration of pre-TCR and Wnt signals for thymocyte survival. Domain-specific TCF-1 allele knock-in mice, Wnt/TCF reporter transgene, pre-TCR signaling analysis Blood Medium 15890681
2010 TCF-1 is required for the establishment of CD8+ memory precursor T cells; its function in generating central memory CD8+ T cells depends on the catenin-binding domain and requires beta-catenin and gamma-catenin as coactivators. Tcf-1 knockout mice, LCMV infection model, secondary challenge, catenin-binding domain mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 20457902
2011 Forced expression of TCF-1 in bone marrow progenitors drives T-lineage cell development even in the absence of Notch1 signals, inducing expression of T cell genes including Gata3, Bcl11b, and TCR components; Notch signals induce TCF-1 which in turn imprints T cell fate. Retroviral forced expression in bone marrow progenitors, T cell development assays in vivo, gene expression profiling Nature High 21814277
2011 TCF-1 represses the IL-17 gene locus via epigenetic modifications (preventing histone hyperacetylation and H3K4 trimethylation at the IL-17 locus) during T cell development in the thymus; this chromatin silencing is established in thymocytes and maintained in peripheral T cells, restricting Th17 differentiation. Tcf-1 knockout mice, chromatin immunoprecipitation (histone modification), EAE model, reconstitution experiments PloS one Medium 21935461
2012 TCF-1 directly represses LEF-1 expression in early thymocytes; loss of TCF-1 leads to aberrant LEF-1 upregulation and T cell malignancy resembling T-ALL, and conditional inactivation of Lef1 greatly delays or prevents T cell malignancy in Tcf7-/- mice. Tcf7 knockout mice, ChIP for TCF-1 binding at Lef1 locus, conditional Lef1 knockout rescue experiments Immunity High 23103132
2012 TCF-1 functions as a self-renewal/differentiation switch in multipotential hematopoietic precursors independently of autocrine Wnt signaling; TCF-1 binds RUNX1 promoter regions and is necessary for production of short but not long RUNX1 isoforms, and the two factors coordinately regulate self-renewal genes. RNA-seq, ChIP-seq, siRNA knockdown, reporter assays in EML hematopoietic cell line PLoS genetics Medium 22412390
2014 TCF-1 and LEF-1 promote the CD4+ T cell fate by directly activating the Th-POK transcription factor; TCF-1 also physically interacts with Runx3 to cooperatively silence the Cd4 gene in CD8+ T cells, establishing distinct genetic mechanisms for CD4 vs. CD8 lineage decisions. DP-specific conditional knockout, ChIP, Co-immunoprecipitation (physical interaction with Runx3), reporter assays Nature immunology High 24836425
2015 TCF-1 directly binds the Bcl6 promoter to promote Bcl-6 expression and the Prdm1 5' regulatory region to repress Blimp1 expression, thereby initiating TFH differentiation by acting upstream of the Bcl-6–Blimp1 axis during acute viral infection. Chromatin immunoprecipitation (ChIP) at Bcl6 and Prdm1 loci, Tcf7 knockout mice, LCMV infection Nature immunology High 26214740
2015 LEF-1 and TCF-1 promote TFH differentiation by sustaining expression of cytokine receptors IL-6Rα and gp130, enhancing ICOS expression, and promoting Bcl6 expression, functioning upstream of the Bcl-6 transcriptional repressor circuit. Selective Lef1 and Tcf7 single and double conditional knockout mice, LEF-1 forced expression, gene expression analysis Nature immunology High 26214741
2015 TCF-1 is required for efficient generation of all innate lymphoid cell (ILC) subsets; upregulation of TCF-1 marks early ILC-committed progenitors (EILPs) that efficiently give rise to NK cells and all helper ILC lineages but lack T and B cell potential. Tcf7 reporter mice, conditional knockout, adoptive transfer, lineage potential assays Nature immunology High 26280998
2018 TCF-1 acts as a lineage-determining transcription factor that establishes the epigenetic identity of T cells by targeting silent chromatin and generating de novo chromatin accessibility; TCF-1 expression in fibroblasts opens chromatin at T cell-restricted gene loci even at regions with repressive marks. ATAC-seq across 8 T cell developmental stages, gain-of-function in fibroblasts, TCF-1 loss-of-function, single-cell chromatin profiling Immunity High 29466756
2018 TCF-1 and HEB co-occupy ~7,000 genomic sites; TCF-1 displaces nucleosomes to promote chromatin accessibility, and TCF-1 inhibits Notch signaling to protect HEB from Notch-mediated proteasomal degradation, enabling cooperative regulation of the DP thymocyte transcriptional and epigenetic program. ChIP-seq, ATAC-seq, proteasome inhibition assays, Notch pathway perturbation, conditional KO Nature immunology High 30420627
2019 TCF-1 mediates the bifurcation between terminal effector (KLRG1hi) and exhausted precursor (KLRG1lo) CD8 T cell fates during chronic infection by repressing terminal effectors, promoting Eomes over T-bet, and driving c-Myb expression to control Bcl-2 and survival; PD-1 stabilizes the TCF-1+ Tex precursor pool. scRNA-seq, lineage tracing, TCF-1 conditional KO, gene expression analysis during LCMV chronic infection Immunity High 31606264
2019 TCF-1 limits Tc17 (IL-17-producing CD8+ T) cell development through sequential suppression of MAF and RORγt transcription factors in double-positive thymocytes, in parallel with TCF-1-driven modulation of chromatin state. TCF-1 conditional KO (DP stage), RNA-seq, ATAC-seq, MAF/RORγt expression analysis The Journal of experimental medicine High 31142588
2019 TCF-1 enforces ILC lineage commitment by binding pre-existing chromatin regulatory elements established in upstream lymphoid precursors in EILPs; TCF-1 is dispensable for specified EILPs but required for committed EILPs and restricts dendritic cell lineage potential. Single-cell transcriptomics, TCF-1 conditional KO, chromatin accessibility profiling (ATAC-seq), adoptive transfer lineage tracing Nature immunology High 31358996
2020 Tcf7 promoter DNA methylation contributes to TCF-1 downregulation in exhausted CD8+ T cells, as demonstrated using an in vitro repeated stimulation exhaustion model where exhausted CTL showed Tcf7 promoter hypermethylation correlating with reduced TCF-1 expression. In vitro exhaustion model, promoter DNA methylation analysis, transcriptomic comparison to in vivo LCMV exhaustion PLoS pathogens Medium 32579593
2021 Regnase-1 directly targets Tcf7 mRNA; its deficiency augments TCF-1 protein expression, promoting formation of TCF-1+ precursor exhausted T cells with upregulated memory and exhaustion markers, and enhancing CAR-T-cell expansion, persistence, and memory-like cell formation. Regnase-1 KO mouse model, phenotypic/transcriptional/epigenetic profiling, human CAR-T xenograft model Blood Medium 33690816
2021 TCF-1 primarily suppresses transcription of genes co-bound by Foxp3 in regulatory T cells; TCF-1 deficiency in Tregs promotes alternative TH17-associated signaling pathways, gut-homing properties, and impairs control of CD4+ T cell polarization and inflammation without altering the core Treg transcriptional signature. Treg-specific TCF-1 conditional KO, scRNA-seq, ChIP-seq, tumor models Nature immunology High 34385712
2022 TCF-1 co-occupancy with the architectural protein CTCF alters topologically associating domain (TAD) structure in T cell progenitors, creating long-range chromatin interactions between previously insulated regulatory elements and target genes; this is linked to H3K27ac deposition and NIPBL recruitment at active enhancers. Hi-C, ChIP-seq, ATAC-seq, TCF-1 gain- and loss-of-function in T cell progenitors Nature immunology High 35726060
2010 Runx2 transcriptionally activates the Tcf7 promoter in chondrocytes (0.3 kb proximal promoter region responsible for Runx2-dependent activation); dominant-negative Tcf7 in Col2a1-expressing chondrocytes causes dwarfism, retarded mineralization, and reduced chondrocyte proliferation, indicating TCF-1 is required for chondrocyte maturation and proliferation downstream of Runx2. Microarray, reporter assays with Tcf7 promoter deletion constructs, dominant-negative transgenic mice, BrdU labeling, in situ hybridization Journal of bone and mineral metabolism Medium 20890621
2009 In normal colon cells, a dominant-negative TCF-1 isoform (dnTCF-1) is equally distributed between nuclear and cytoplasmic compartments, whereas in colon cancer cells TCF-1 is predominantly cytoplasmic due to active nuclear export directed by an autocrine Wnt ligand that requires CaMKII activity for secretion. Immunofluorescence, nuclear export inhibition, CaMKII inhibition, Wnt ligand blocking in colon cancer vs. normal cells Oncogene Medium 19749792
2010 IL-4 signaling via STAT6 downregulates TCF-1 expression in human naive CD4+ T cells, preferentially suppressing the shorter dominant-negative TCF-1 isoforms; STAT6 directly binds the TCF-1 regulatory region as shown by EMSA and ChIP. EMSA, ChIP, STAT6 knockdown, qPCR, cytokine treatment of primary human T cells The Journal of biological chemistry Medium 20980261
2015 miR-22-3p binds to the 3' UTR of TCF7 mRNA and downregulates its expression; knockdown of TCF7 in hepatocytes upregulates gluconeogenic genes, and in vivo antagomiR-mediated silencing of miR-22-3p restores hepatic TCF7 and reduces gluconeogenesis in diabetic mice. Luciferase 3'UTR reporter assay, siRNA knockdown, antagomiR in vivo, gluconeogenic gene expression Diabetes Medium 26193896
2017 The deubiquitinase Uch37 interacts with TCF-1 (Tcf7) and its deubiquitinase activity is required for Tcf7 association with target gene promoters (chromatin occupancy), without affecting TCF-1 protein stability, thereby activating Wnt/beta-catenin target gene expression in Xenopus embryos and human liver cancer cells. Co-immunoprecipitation, ChIP in Xenopus embryo and HCC cells, Uch37 knockdown/overexpression, deubiquitinase activity mutants Scientific reports Medium 28198400
2015 TCF7 is a direct target of miR-34a; ectopic miR-34a inhibits bone metastasis in Ras-activated prostate cancer and reduces TCF7-driven WNT signaling; TCF7 itself has oncogenic properties in prostate cancer cells promoting androgen-independent proliferation. miR-34a ectopic expression, xenograft model, WNT gene signature analysis, TCF7 expression correlation with miR-34a Oncotarget Low 25436980
2015 AF1q specifically binds to TCF7 protein in the Wnt signaling pathway and results in transcriptional activation of CD44 and downstream TCF7/LEF1 targets; AF1q promotes breast cancer proliferation, migration, mammosphere formation, and metastasis through the AF1q/TCF7/CD44 axis. Co-immunoprecipitation (AF1q–TCF7 interaction), reporter/gene expression assays, xenograft models Oncotarget Low 26079538
2018 TCF-1 functions in brown adipocytes to modulate Gprc6a and Ucp1 promoter activation independent of beta-catenin, requiring PRDM16 and the histone demethylase LSD1 as coactivators, as part of an osteocalcin-GPRC6A-TCF7 feedback axis in thermogenesis. Overexpression and knockdown of Tcf7, promoter reporter assays, co-factor interaction studies in brown adipocytes Molecular and cellular biology Low 29358218
2014 TCF-1-mediated Wnt signaling activates alpha-defensin HD-5 and HD-6 transcription in Paneth cells via three distinct TCF binding sites in the defensin promoters; binding of TCF-1 to these motifs was confirmed by EMSA, and TCF-1 cooperates with beta-catenin to activate transcription. Reporter gene assays, EMSA, promoter binding analysis, Tcf-1 knockout mice (cryptdin expression) American journal of physiology. Gastrointestinal and liver physiology Medium 24994854
2020 A 1 kb regulatory element containing a Notch binding site is crucial for initiation of Tcf7 expression in T cells and innate lymphoid cells, but different transcriptional controllers use this same element in T cells vs. ILCs; Notch binding is required for Tcf7 initiation in T cells but not in ILCs. Regulatory element deletion analysis, reporter mice, Notch binding site mutation, Tcf7 expression in multiple lineages Frontiers in immunology Medium 32265924
2022 Single-cell CRISPR disruption of Tcf7 in early T cell progenitors reveals a kinetic tug-of-war with progenitor factors Spi1/Bcl11a, where Tcf7 functions before T lineage commitment to regulate developmental speed and cell fate choices at the DN1 stage. Single-cell CRISPR disruption, scRNA-seq, synchronized in vitro differentiation Science immunology Medium 35594339
2020 Tcf7hi effector-phase CD8+ T cells show no evidence of prior cytolytic differentiation and quantitatively give rise to central memory T cells based on lineage tracing; mechanistically, Tcf1 counteracts Tcf7hi cell differentiation and sustains expression of conserved adult stem-cell genes critical for CD8 T cell stemness. Lineage tracing, scRNA-seq, Tcf7 conditional KO, gene expression analysis during acute infection Immunity Medium 33128876
2021 CRISPR-Cas9 editing of TCF-1 in human primary T cells directly reduces expansion capacity, demonstrating a cell-intrinsic role for TCF-1 in regulating the secondary expansion (stem-like memory) property of HIV-specific CD8+ T cells. CRISPR-Cas9 editing of TCF-1 in human primary T cells, expansion assays JCI insight Medium 33351785
2022 TGF-β signaling maintains the stem-like state and quiescence of PD-1+ TCF-1+ CD8 T cells during chronic LCMV infection; TGF-β regulates the unique transcriptional program of these cells including upregulation of inhibitory receptors specifically expressed on them, and promotes terminal differentiation of exhausted CD8 T cells by suppressing the effector program. TGF-β receptor conditional KO in virus-specific CD8 T cells, transcriptomic analysis, LCMV chronic infection model The Journal of experimental medicine Medium 35980386
2021 IL-10R–STAT3 signaling maintains the PD-1int TCF-1+ CD8+ T cell population; inhibition of IL-10R signaling alters chromatin accessibility and disrupts NFAT/AP-1 cooperativity, promoting an NFAT-associated exhaustion program and accumulation of PD-1hi cells. Il10rb/Stat3 conditional KO, scRNA-seq, ATAC-seq, CLL mouse model Immunity Medium 34879221
2023 IL-33–ST2 signaling is pivotal for expansion and maintenance of stem-like TCF-1+ CD8+ T cells during chronic viral infection; ST2-deficient CD8+ T cells show biased terminal differentiation and premature loss of Tcf-1, effects rescued by blockade of type I interferon; IL-33 broadly augments chromatin accessibility in TCF-1+ stem-like cells. ST2-KO mice, chronic LCMV infection, ATAC-seq, type I IFN blockade rescue, lineage tracing Immunity Medium 36809763
2017 The androgen receptor suppresses TCF7 expression partly through induction of miR-1 which targets TCF7 mRNA; TCF7 overexpression or disruption of miR-1 function promotes androgen-independent proliferation in prostate cancer, demonstrating TCF7 as an oncogenic factor controlled by the AR-miR-1 axis. miR-1 overexpression, TCF7 overexpression/knockdown, xenograft model, clinical dataset analysis Prostate cancer and prostatic diseases Low 28220803

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision. Immunity 555 31606264
1991 Identification and cloning of TCF-1, a T lymphocyte-specific transcription factor containing a sequence-specific HMG box. The EMBO journal 512 1989880
2011 A critical role for TCF-1 in T-lineage specification and differentiation. Nature 336 21814277
2010 Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory. Proceedings of the National Academy of Sciences of the United States of America 304 20457902
2015 LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nature immunology 286 26214741
2015 TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nature immunology 241 26280998
1993 Differential expression of the HMG box factors TCF-1 and LEF-1 during murine embryogenesis. Development (Cambridge, England) 228 8223271
2021 Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes. Immunity 222 34534439
2001 The beta-catenin--TCF-1 pathway ensures CD4(+)CD8(+) thymocyte survival. Nature immunology 201 11477404
1992 Sequence-specific interaction of the HMG box proteins TCF-1 and SRY occurs within the minor groove of a Watson-Crick double helix. The EMBO journal 199 1639073
2015 The transcription factor TCF-1 initiates the differentiation of T(FH) cells during acute viral infection. Nature immunology 198 26214740
1998 Critical involvement of Tcf-1 in expansion of thymocytes. Journal of immunology (Baltimore, Md. : 1950) 187 9780167
1996 Extensive alternative splicing and dual promoter usage generate Tcf-1 protein isoforms with differential transcription control properties. Molecular and cellular biology 175 8622675
2018 Lineage-Determining Transcription Factor TCF-1 Initiates the Epigenetic Identity of T Cells. Immunity 169 29466756
2021 Circ3823 contributes to growth, metastasis and angiogenesis of colorectal cancer: involvement of miR-30c-5p/TCF7 axis. Molecular cancer 157 34172072
1993 The hLEF/TCF-1 alpha HMG protein contains a context-dependent transcriptional activation domain that induces the TCR alpha enhancer in T cells. Genes & development 157 8253387
2001 Wnt signaling is required for thymocyte development and activates Tcf-1 mediated transcription. European journal of immunology 154 11265645
2020 Central memory CD8+ T cells derive from stem-like Tcf7hi effector cells in the absence of cytotoxic differentiation. Immunity 153 33128876
2012 The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T cell development and malignancy. Immunity 152 23103132
2014 TCF-1 and LEF-1 act upstream of Th-POK to promote the CD4(+) T cell fate and interact with Runx3 to silence Cd4 in CD8(+) T cells. Nature immunology 142 24836425
2008 Insertional mutagenesis by the Tol2 transposon-mediated enhancer trap approach generated mutations in two developmental genes: tcf7 and synembryn-like. Development (Cambridge, England) 139 18065431
1991 Cloning of murine TCF-1, a T cell-specific transcription factor interacting with functional motifs in the CD3-epsilon and T cell receptor alpha enhancers. The Journal of experimental medicine 137 1827138
1990 Purification of TCF-1 alpha, a T-cell-specific transcription factor that activates the T-cell receptor C alpha gene enhancer in a context-dependent manner. The New biologist 117 2083253
2013 TCF-1 controls ILC2 and NKp46+RORγt+ innate lymphocyte differentiation and protection in intestinal inflammation. Journal of immunology (Baltimore, Md. : 1950) 112 24038093
1996 Involvement of transcription factors TCF-1 and GATA-3 in the initiation of the earliest step of T cell development in the thymus. The Journal of experimental medicine 112 9064330
2021 Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity. Immunity 98 34879221
2019 The transcription factor TCF-1 enforces commitment to the innate lymphoid cell lineage. Nature immunology 97 31358996
2004 IL-7 receptor signals inhibit expression of transcription factors TCF-1, LEF-1, and RORgammat: impact on thymocyte development. The Journal of experimental medicine 97 15365098
2022 In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue. The Journal of experimental medicine 92 35472220
2021 Role of TCF-1 in differentiation, exhaustion, and memory of CD8+ T cells: A review. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 87 33913198
2012 Tcf7 is an important regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line. PLoS genetics 85 22412390
2019 Control of Lymphocyte Fate, Infection, and Tumor Immunity by TCF-1. Trends in immunology 84 31734149
2015 MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer. Oncotarget 83 25436980
2020 HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells. Nature immunology 76 32066947
2021 Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood 74 33690816
2021 TCF-1 regulates HIV-specific CD8+ T cell expansion capacity. JCI insight 73 33351785
2015 Elevated Hepatic miR-22-3p Expression Impairs Gluconeogenesis by Silencing the Wnt-Responsive Transcription Factor Tcf7. Diabetes 70 26193896
2022 BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4+ T cell responses to persistent antigen. Immunity 68 35637103
2018 Human Lymph Nodes Maintain TCF-1hi Memory T Cells with High Functional Potential and Clonal Diversity throughout Life. Journal of immunology (Baltimore, Md. : 1950) 68 30111633
1999 Clonal acquisition of the Ly49A NK cell receptor is dependent on the trans-acting factor TCF-1. Immunity 68 10549625
2012 β-catenin/TCF-1 pathway in T cell development and differentiation. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 67 22535304
2022 TGF-β regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection. The Journal of experimental medicine 66 35980386
2021 TCF-1 controls Treg cell functions that regulate inflammation, CD8+ T cell cytotoxicity and severity of colon cancer. Nature immunology 65 34385712
1999 Tcf-1-mediated transcription in T lymphocytes: differential role for glycogen synthase kinase-3 in fibroblasts and T cells. International immunology 65 10221643
2022 TCF-1: a maverick in T cell development and function. Nature immunology 64 35487986
2014 Multiple tumor suppressor microRNAs regulate telomerase and TCF7, an important transcriptional regulator of the Wnt pathway. PloS one 62 24551047
2015 Inhibition of β-catenin signaling suppresses pancreatic tumor growth by disrupting nuclear β-catenin/TCF-1 complex: critical role of STAT-3. Oncotarget 59 25869100
2020 Rapid in vitro generation of bona fide exhausted CD8+ T cells is accompanied by Tcf7 promotor methylation. PLoS pathogens 58 32579593
2023 STING signaling promotes NK cell antitumor immunity and maintains a reservoir of TCF-1+ NK cells. Cell reports 56 37708030
2003 Redundant functions of TCF-1 and LEF-1 during T and NK cell development, but unique role of TCF-1 for Ly49 NK cell receptor acquisition. European journal of immunology 56 12731066
2018 TCF-1 and HEB cooperate to establish the epigenetic and transcription profiles of CD4+CD8+ thymocytes. Nature immunology 55 30420627
2023 Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1+ PD-1+ CD8 T cells. Science immunology 54 37624910
2022 TCF-1 promotes chromatin interactions across topologically associating domains in T cell progenitors. Nature immunology 54 35726060
2005 Cooperating pre-T-cell receptor and TCF-1-dependent signals ensure thymocyte survival. Blood 54 15890681
2016 Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus. Cell reports 48 27806296
1995 The human TCF-1 gene encodes a nuclear DNA-binding protein uniquely expressed in normal and neoplastic T-lineage lymphocytes. Blood 48 7579399
2019 TCF-1 limits the formation of Tc17 cells via repression of the MAF-RORγt axis. The Journal of experimental medicine 47 31142588
2003 Loss of expression of the WNT/beta-catenin-signaling pathway transcription factors lymphoid enhancer factor-1 (LEF-1) and T cell factor-1 (TCF-1) in a subset of peripheral T cell lymphomas. The American journal of pathology 45 12707037
1991 TCF-1, a T cell-specific transcription factor of the HMG box family, interacts with sequence motifs in the TCR beta and TCR delta enhancers. International immunology 45 1836958
2011 Critical role of TCF-1 in repression of the IL-17 gene. PloS one 44 21935461
2003 Beta-catenin/Tcf-1-mediated transactivation of cyclin D1 promoter is negatively regulated by thyroid hormone. Biochemical and biophysical research communications 43 12951064
2023 The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1+ CD8+ T cells in chronic viral infection. Immunity 42 36809763
2014 TCF-1-mediated Wnt signaling regulates Paneth cell innate immune defense effectors HD-5 and -6: implications for Crohn's disease. American journal of physiology. Gastrointestinal and liver physiology 40 24994854
2009 A Wnt kinase network alters nuclear localization of TCF-1 in colon cancer. Oncogene 40 19749792
2022 Single-cell deletion analyses show control of pro-T cell developmental speed and pathways by Tcf7, Spi1, Gata3, Bcl11a, Erg, and Bcl11b. Science immunology 39 35594339
2022 Wnt-TCF7-SOX9 axis promotes cholangiocarcinoma proliferation and pemigatinib resistance in a FGF7-FGFR2 autocrine pathway. Oncogene 38 35428876
2016 Upregulation of miR-192 inhibits cell growth and invasion and induces cell apoptosis by targeting TCF7 in human osteosarcoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 38 27683056
2015 Identification of a novel mechanism of action of fingolimod (FTY720) on human effector T cell function through TCF-1 upregulation. Journal of neuroinflammation 37 26714756
2007 The candidate genes TAF5L, TCF7, PDCD1, IL6 and ICAM1 cannot be excluded from having effects in type 1 diabetes. BMC medical genetics 37 18045485
1992 Identification of a core motif that is recognized by three members of the HMG class of transcriptional regulators: IRE-ABP, SRY, and TCF-1 alpha. Journal of cellular biochemistry 37 1618927
2003 A polymorphism in the TCF7 gene, C883A, is associated with type 1 diabetes. Diabetes 36 12765974
2022 Pancreatic stellate cells exploit Wnt/β-catenin/TCF7-mediated glutamine metabolism to promote pancreatic cancer cells growth. Cancer letters 35 36565920
2015 AF1q is a novel TCF7 co-factor which activates CD44 and promotes breast cancer metastasis. Oncotarget 35 26079538
2020 A Shared Regulatory Element Controls the Initiation of Tcf7 Expression During Early T Cell and Innate Lymphoid Cell Developments. Frontiers in immunology 33 32265924
2002 Inactivation of Apc perturbs mammary development, but only directly results in acanthoma in the context of Tcf-1 deficiency. Oncogene 33 12226748
2019 Opposing roles of TCF7/LEF1 and TCF7L2 in cyclin D2 and Bmp4 expression and cardiomyocyte cell cycle control during late heart development. Laboratory investigation; a journal of technical methods and pathology 30 30778164
2018 Long non-coding RNA TCF7 contributes to the growth and migration of airway smooth muscle cells in asthma through targeting TIMMDC1/Akt axis. Biochemical and biophysical research communications 29 30528236
2016 Long noncoding RNA TCF7 promotes invasiveness and self-renewal of human non-small cell lung cancer cells. Human cell 29 27766570
2009 Evidence for association of the TCF7 locus with type I diabetes. Genes and immunity 29 19956102
2005 lin-17/Frizzled and lin-18 regulate POP-1/TCF-1 localization and cell type specification during C. elegans vulval development. Developmental biology 29 15649465
2023 Dihydroartemisinin inhibits the development of colorectal cancer by GSK-3β/TCF7/MMP9 pathway and synergies with capecitabine. Cancer letters 28 38101610
2021 TCF-1 maintains CD8+ T cell stemness in tumor microenvironment. Journal of leukocyte biology 28 34047386
2021 Saikosaponin-d Alleviates Renal Inflammation and Cell Apoptosis in a Mouse Model of Sepsis via TCF7/FOSL1/Matrix Metalloproteinase 9 Inhibition. Molecular and cellular biology 28 34309413
2018 The Disruption of the β-Catenin/TCF-1/STAT3 Signaling Axis by 4-Acetylantroquinonol B Inhibits the Tumorigenesis and Cancer Stem-Cell-Like Properties of Glioblastoma Cells, In Vitro and In Vivo. Cancers 28 30563094
2010 Inhibition of suppressive T cell factor 1 (TCF-1) isoforms in naive CD4+ T cells is mediated by IL-4/STAT6 signaling. The Journal of biological chemistry 28 20980261
2005 Expression pattern of zebrafish tcf7 suggests unexplored domains of Wnt/beta-catenin activity. Developmental dynamics : an official publication of the American Association of Anatomists 28 15765502
1997 Ectopic activation of lymphoid high mobility group-box transcription factor TCF-1 and overexpression in colorectal cancer cells. International journal of cancer 28 9259402
2018 Down-regulation of lncTCF7 inhibits cell migration and invasion in colorectal cancer via inhibiting TCF7 expression. Human cell 27 30225781
2014 Wnt signaling transcription factors TCF-1 and LEF-1 are upregulated in malignant astrocytic brain tumors. Histology and histopathology 27 24858819
2012 Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and β-catenin interactions. The Journal of clinical investigation 27 22466651
2010 Regulation of Tcf7 by Runx2 in chondrocyte maturation and proliferation. Journal of bone and mineral metabolism 27 20890621
1992 A common ancestor of the mammalian transcription factors TCF-1 and TCF-1 alpha/LEF-1 expressed in chicken T cells. European journal of immunology 27 1577072
2023 BET inhibitors rescue anti-PD1 resistance by enhancing TCF7 accessibility in leukemia-derived terminally exhausted CD8+ T cells. Leukemia 26 36681742
2017 TCF7 is suppressed by the androgen receptor via microRNA-1-mediated downregulation and is involved in the development of resistance to androgen deprivation in prostate cancer. Prostate cancer and prostatic diseases 26 28220803
2020 Exploring the stage-specific roles of Tcf-1 in T cell development and malignancy at single-cell resolution. Cellular & molecular immunology 25 32868912
2017 Ubiquitin C-terminal hydrolase37 regulates Tcf7 DNA binding for the activation of Wnt signalling. Scientific reports 24 28198400
2017 Andrographolide Induces Cell Cycle Arrest and Apoptosis of Chondrosarcoma by Targeting TCF-1/SOX9 Axis. Journal of cellular biochemistry 24 28485543
2003 Tcf-1 expression during Xenopus development. Gene expression patterns : GEP 23 12711535
2021 Soybean-derived gma-miR159a alleviates colon tumorigenesis by suppressing TCF7/MYC in mice. The Journal of nutritional biochemistry 22 33705946
2018 T Cell Factor 7 (TCF7)/TCF1 Feedback Controls Osteocalcin Signaling in Brown Adipocytes Independent of the Wnt/β-Catenin Pathway. Molecular and cellular biology 22 29358218