Affinage

TCF7L2

Transcription factor 7-like 2 · UniProt Q9NQB0

Length
619 aa
Mass
67.9 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TCF7L2 (TCF-4) is an HMG-box transcription factor that serves as the principal nuclear effector of canonical Wnt signaling, binding β-catenin through its N-terminal first 50 residues and directing transcriptional activation or repression of target genes that govern proliferation, differentiation, and metabolism (PMID:11711551, PMID:9784592). Its co-regulatory output is tuned by competing partners: plakoglobin binds an adjacent N-terminal site (residues 51–80) and dampens activity in a manner controlled by CK2 phosphorylation at Ser-58/59/60 (PMID:11711551), HIC1 sequesters TCF-4/β-catenin into nuclear bodies away from Wnt-responsive elements (PMID:16724116), and TIS7 recruits histone deacetylase complexes to repress TCF-4 output (PMID:16204248). In the intestine, TCF-4 maintains the proliferative crypt compartment by repressing p21(CIP1/WAF1) through c-MYC, and its disruption triggers G1 arrest and differentiation (PMID:12408868, PMID:9916915); it also drives Paneth cell α-defensin expression, with reduced binding underlying diminished antimicrobial output in ileal Crohn's disease (PMID:17709525). Genome-wide, TCF7L2 directly binds and regulates large programs of glucose, lipid, and amino acid metabolic genes, acting through interplay with HNF4α in liver (PMID:25414334) and across adipocytes where loss of its HMG-box DNA-binding function produces glucose intolerance, insulin resistance, and adipocyte hypertrophy (PMID:29317436, PMID:30948248). In the pancreas it controls β-cell insulin secretion and mass via an ISL1-centered network and by repressing PIK3R1 to activate PI3K/AKT (PMID:22717537, PMID:25015099, PMID:31312258), supports α-cell glucagon secretion and counter-regulation (PMID:28343277), and acts non-cell-autonomously through pericytic BMP4 (PMID:29246974); in liver it represses gluconeogenesis downstream of insulin by blocking CREB/CRTC2/FoxO1 promoter occupancy (PMID:23028378, PMID:22967502). In the nervous system TCF7L2 functions as a thalamic terminal selector (PMID:32675279), drives astrocyte maturation and synapse-number restriction (PMID:37798419), promotes oligodendrocyte differentiation by directly repressing BMP4 (PMID:33452226), and in the medial habenula links nicotine to glucose homeostasis through a polysynaptic brain-pancreas circuit (PMID:31619789).

Mechanistic history

Synthesis pass · year-by-year structured walk · 32 steps
  1. 1998 Medium

    Established that TCF-4 physically binds β-catenin and drives its nuclear localization, placing TCF-4 as a Wnt pathway transcriptional partner with spatially defined developmental expression.

    Evidence Co-IP of TCF-4 with β-catenin, in situ hybridization, and Pax-6 epistasis in mouse embryos

    PMID:9784592

    Open questions at the time
    • Direct target genes not defined
    • Functional consequence of nuclear β-catenin recruitment not tested in this study
  2. 1999 Medium

    Localized TCF-4 protein to the proliferative crypt and mammary epithelium with a crypt-villus gradient, anchoring its inferred role in proliferative compartment maintenance.

    Evidence IHC with TCF-4-specific monoclonal antibodies on mouse and human tissue

    PMID:9916915

    Open questions at the time
    • No functional perturbation in this study
    • Does not establish which target genes drive the proliferative role
  3. 2001 High

    Resolved the bipartite N-terminal architecture of TCF-4 and its phospho-regulation, showing β-catenin and plakoglobin bind distinct sites and CK2 phosphorylation selectively reduces inhibitory plakoglobin binding.

    Evidence In vitro CK2 kinase assay, deletion mapping, Co-IP, ternary complex reconstitution, and mutant transcriptional assays

    PMID:11711551

    Open questions at the time
    • In vivo relevance of CK2 phosphorylation not established
    • Effect on specific endogenous target genes not tested
  4. 2001 High

    Demonstrated TCF-4 can act as a direct transcriptional repressor (of osteopontin) and that DNA decoy sequences titrating endogenous TCF-4 de-repress targets to promote metastasis, showing context-dependent repressive output.

    Evidence EMSA, OPN promoter-reporter cotransfection, and in vivo syngeneic rat metastasis assay

    PMID:11454716

    Open questions at the time
    • Co-regulator partners mediating repression not defined here
    • Generalizability across promoters not addressed
  5. 2002 High

    Defined the core intestinal mechanism: β-catenin/TCF-4 maintains proliferation by repressing p21 via c-MYC, and its loss drives G1 arrest and differentiation.

    Evidence Dominant-negative TCF-4 in CRC lines with reporter and expression analyses

    PMID:12408868

    Open questions at the time
    • Does not address normal homeostatic crypt dynamics in vivo
    • Other downstream targets contributing to differentiation not enumerated
  6. 2006 High

    Identified a negative regulatory mechanism in which HIC1 sequesters TCF-4/β-catenin into nuclear bodies, spatially uncoupling the complex from Wnt-responsive promoters.

    Evidence Reciprocal Co-IP, nuclear body co-localization imaging, and TOPflash reporter assays

    PMID:16724116

    Open questions at the time
    • Stoichiometry and dynamics of sequestration unresolved
    • Physiological contexts where HIC1 controls TCF-4 not mapped
  7. 2005 Medium

    Showed TCF-4 output is repressed by TIS7-mediated recruitment of HDAC complexes, providing a chromatin-modifying brake on β-catenin/TCF-4 transcription.

    Evidence TOPflash assay, Co-IP with active HDACs, and TIS7 KO MEF gene expression analysis

    PMID:16204248

    Open questions at the time
    • Direct vs indirect TIS7-TCF-4 contact not fully resolved
    • Single lab
  8. 2007 High

    Established TCF7L2 as a causal regulator of Paneth cell α-defensin expression, linking reduced TCF7L2 binding to impaired antimicrobial defense in ileal Crohn's disease.

    Evidence Quantitative promoter binding assay, Tcf-4 heterozygous KO mice, and bacterial killing assays

    PMID:17709525

    Open questions at the time
    • Whether the human disease association is causal or correlative not settled
    • Direct defensin promoter occupancy in vivo not shown
  9. 2011 Medium

    Connected TCF7L2 to oligodendrocyte biology, showing remyelination-specific expression and a selective Olig2 (not Olig1) protein complex.

    Evidence Co-IP and cuprizone demyelination/remyelination mouse model with temporal expression

    PMID:22160878

    Open questions at the time
    • Functional consequence of the Olig2 complex not tested here
    • Direct target genes in oligodendrocytes not identified
  10. 2011 Medium

    Dissected TCF7L2 splice-variant function in β-cells, showing isoform-specific opposite effects on survival, function, and Wnt activity, with depletion activating GSK3β.

    Evidence Variant overexpression/knockdown in human islets, apoptosis and GSIS assays, TOPflash, GSK3β activity

    PMID:21357677

    Open questions at the time
    • Endogenous isoform ratios in disease not quantified
    • Single lab
  11. 2012 High

    Demonstrated a cell-autonomous β-cell requirement for TCF7L2 in glucose-stimulated insulin secretion, incretin response, and mass expansion.

    Evidence Pdx1-Cre conditional KO, GTT, isolated islet GSIS, and beta cell mass tomography

    PMID:22717537

    Open questions at the time
    • Direct islet target genes not defined in this study
    • Relation to T2D risk allele not addressed here
  12. 2012 High

    Defined a hepatic anti-gluconeogenic mechanism: TCF7L2 binds gluconeogenic promoters and blocks CREB/CRTC2/FoxO1 occupancy, with knockdown raising glucose and a nuclear isoform rescuing hyperglycemia.

    Evidence ChIP, siRNA knockdown, adenoviral overexpression, and in vivo GTT

    PMID:23028378

    Open questions at the time
    • Co-regulator basis of CREB/FoxO1 displacement unresolved
    • Isoform-specific contributions not fully separated
  13. 2012 Medium

    Placed hepatic TCF7L2 downstream of insulin signaling as a repressor of gluconeogenesis, with insulin inducing TCF7L2 and β-catenin Ser675 phosphorylation.

    Evidence Hepatocyte siRNA, in vivo lithium Wnt activation, TOPGAL reporter, and glucose production assays

    PMID:22967502

    Open questions at the time
    • Direct insulin-to-TCF7L2 transcriptional link not fully mapped
    • Single lab
  14. 2012 Medium

    Linked TCF7L2 overexpression to ductal-to-islet regeneration via JAK2/STAT3, expanding its role to β-cell neogenesis.

    Evidence Adenoviral overexpression in exocrine cells with JAK2/STAT3 inhibition and in vivo HFD/STZ models

    PMID:22945304

    Open questions at the time
    • Physiological contribution of this pathway uncertain
    • Single lab
  15. 2014 Medium

    Defined a pancreatic islet transcriptional network in which ISL1 is a primary direct TCF7L2 target controlling proinsulin production, and linked the rs7903146 risk allele to altered TCF7L2 expression and insulin content.

    Evidence RNA-seq of rodent and human islets with TCF7L2 manipulation and genotype-stratified human islet profiling

    PMID:25015099

    Open questions at the time
    • Direction of allelic effect on TCF7L2 activity debated
    • Single lab
  16. 2014 High

    Mapped genome-wide direct hepatic TCF7L2 targets and revealed mutual antagonism with HNF4α in metabolic gene regulation.

    Evidence ChIP-seq, time-course RNA-seq after silencing, and co-siRNA epistasis for HNF4α

    PMID:25414334

    Open questions at the time
    • Mechanism of HNF4α chromatin displacement not resolved
    • In vivo confirmation of the HNF4α interplay limited
  17. 2015 Medium

    Linked LRP6-dependent Wnt signaling to TCF7L2 activity in vascular smooth muscle, where diminished TCF7L2 promotes Sp1/PDGF-driven dedifferentiation rescuable by Wnt3a.

    Evidence LRP6(R611C) knock-in mice, carotid injury model, and Wnt3a rescue

    PMID:26489464

    Open questions at the time
    • Direct TCF7L2 VSMC targets not defined
    • Single lab
  18. 2016 Medium

    Showed TCF7L2 is required for thalamic-specific lithium-induced nuclear translocation of β-catenin, establishing a tissue-selective gating of Wnt nuclear signaling.

    Evidence Lentiviral silencing, ectopic expression in cortical neurons, nuclear fractionation, and zebrafish behavioral knockdown

    PMID:27793772

    Open questions at the time
    • Molecular basis of thalamic specificity unresolved
    • Single lab
  19. 2017 High

    Established a cell-autonomous α-cell role for TCF7L2 in glucagon secretion, α-cell mass, and counter-regulatory hypoglycemic responses.

    Evidence Alpha cell-selective KO with hyperinsulinaemic-hypoglycaemic clamp and islet glucagon assays

    PMID:28343277

    Open questions at the time
    • Direct α-cell target genes not enumerated
    • Mechanism of low-glucose secretion control unresolved
  20. 2017 High

    Revealed a paracrine mechanism: pericytic TCF7L2 supports β-cell function via secreted factors including BMP4, with exogenous BMP4 rescuing impaired insulin secretion.

    Evidence Pericyte-specific conditional KO, GTT, islet GSIS, and BMP4 rescue

    PMID:29246974

    Open questions at the time
    • Full secretome mediating the effect not defined
    • Direct BMP4 promoter regulation in pericytes not shown
  21. 2018 High

    Established that TCF7L2 HMG-box DNA-binding function in adipocytes regulates Wnt signaling during adipogenesis and is required for systemic glucose homeostasis.

    Evidence 3T3-L1 adipogenesis assays, adipocyte-specific HMG-box deletion mice, ChIP-seq, and RNA-seq

    PMID:29317436

    Open questions at the time
    • Distinction between DNA-binding-dependent and -independent functions incomplete
    • Specific causal adipocyte targets not pinpointed
  22. 2018 Medium

    Showed TCF7L2 directly represses PIK3R1 to activate PI3K/AKT and stimulate β-cell insulin secretion.

    Evidence ChIP-PCR, luciferase reporter, knockdown/overexpression, and insulin secretion ELISA

    PMID:31312258

    Open questions at the time
    • In vivo confirmation lacking
    • Single lab
  23. 2018 Medium

    Identified TCF7L2/EGR1 synergistic activation of LCN2 via ERK signaling in a positive feedback loop, extending TCF7L2 to ERK-coupled transcription.

    Evidence ChIP, deletion-mapped reporters, MEK inhibitor epistasis, and migration/invasion assays

    PMID:30557604

    Open questions at the time
    • Physiological relevance of the loop unestablished
    • Single lab
  24. 2019 High

    Defined adipocyte-autonomous TCF7L2 control of lipid and glucose metabolic genes, with deletion causing hypertrophy, insulin resistance, and impaired lipolysis.

    Evidence Adipoq-Cre KO, HFD challenge, ChIP-seq, RNA-seq, and lipolysis assays

    PMID:30948248

    Open questions at the time
    • Hierarchy of direct vs secondary metabolic targets incomplete
    • Crosstalk with hepatic phenotype not dissected
  25. 2019 Medium

    Showed MALAT1 enhances TCF7L2 mRNA translation via SRSF1 and the mTORC1-4EBP1 axis, adding a post-transcriptional layer to TCF7L2 regulation relevant to glucose metabolism and tumorigenicity.

    Evidence Polysome fractionation, 5′UTR reporters, mTOR inhibition, and siRNA epistasis

    PMID:30914432

    Open questions at the time
    • Direct MALAT1-TCF7L2 mRNA interaction not fully demonstrated
    • Single lab
  26. 2019 High

    Established a brain-pancreas axis in which medial habenular TCF7L2 regulates nicotinic receptor function and nicotine-induced glucose dysregulation through a polysynaptic mHb-to-pancreas circuit.

    Evidence Viral mHb inhibition, nicotine self-administration, circuit tracing, and mutant Tcf7l2 rats

    PMID:31619789

    Open questions at the time
    • Transcriptional targets mediating nAChR control not defined
    • Molecular link from mHb signaling to islet output incomplete
  27. 2020 High

    Defined TCF7L2 as a thalamic terminal selector controlling postmitotic differentiation, connectivity, and firing properties through direct target genes.

    Evidence Embryonic and postnatal conditional KO, electrophysiology, ChIP, and RNA-seq

    PMID:32675279

    Open questions at the time
    • Full direct target set incompletely catalogued
    • Mechanism of terminal-selector specificity unresolved
  28. 2020 Medium

    Showed adipocyte TCF7L2 loss produces sexually dimorphic glucose intolerance and altered incretin/NEFA profiles, implicating adipocyte-to-islet/enteroendocrine crosstalk.

    Evidence Adipoq-Cre KO with chow/HFD, GSIS, incretin and lipid measurements

    PMID:33068125

    Open questions at the time
    • Proposed paracrine/endocrine mediators not directly demonstrated
    • Basis of sex dimorphism unknown
  29. 2021 High

    Defined the oligodendrocyte differentiation mechanism: TCF7L2 directly represses Bmp4, and BMP4 deletion rescues differentiation arrested by TCF7L2 loss.

    Evidence Oligodendrocyte and BMP4 conditional KOs, compound genetic epistasis, ChIP, and in vitro differentiation

    PMID:33452226

    Open questions at the time
    • Co-factors at the Bmp4 element not identified
    • Wnt-dependence of this repression not fully resolved
  30. 2021 Low

    Associated VSMC TCF7L2 upregulation with BCL2 repression and apoptosis as a candidate driver of thoracic aortic aneurysm, supported by aortic eQTL colocalization.

    Evidence In vitro VSMC overexpression with BCL2 readout and eQTL colocalization

    PMID:34265237

    Open questions at the time
    • Single in vitro molecular readout (BCL2); no in vivo causal test
    • Direct BCL2 promoter regulation not shown
    • Disease link rests on colocalization
  31. 2022 Medium

    Causally linked impaired TCF7L2-dependent transcription to poor myelination in Huntington's disease by restoring remyelination with Tcf7l2 overexpression.

    Evidence RNA-seq/proteomics of HD white matter and in vivo Tcf7l2 overexpression rescue in R6/2 mice

    PMID:36044851

    Open questions at the time
    • Mechanism repressing TCF7L2 in HD unresolved
    • Single lab
  32. 2023 High

    Established TCF7L2 as the dominant astrocytic Wnt effector controlling astrocyte maturation, tiling, gap-junction coupling, and synapse-number restriction with behavioral consequences.

    Evidence Postnatal astrocyte-specific conditional KO with morphology, coupling, synapse, and behavioral assays

    PMID:37798419

    Open questions at the time
    • Direct astrocytic target genes restricting synapse number not defined
    • Molecular link to behavioral phenotype incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TCF7L2 selects activation versus repression and tissue-specific direct target sets across its many roles, and which co-regulator/isoform configurations drive each context, remains unresolved.
  • Unified model linking isoform/co-regulator composition to activator vs repressor output is lacking
  • Tissue-specific direct target catalogs only partially defined
  • Mechanism of tissue-selective β-catenin gating not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 6 GO:0060089 molecular transducer activity 2
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1430728 Metabolism 4
Partners
CTNNB1EGR1HIC1HNF4AJUPOLIG2

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 The β-catenin/TCF-4 complex controls proliferation versus differentiation in intestinal epithelial cells by directly repressing p21(CIP1/WAF1) transcription through c-MYC; disruption of β-catenin/TCF-4 activity decreases c-MYC expression, releases p21(CIP1/WAF1) transcription, and induces G1 arrest and differentiation. Dominant-negative TCF-4 expression in CRC cell lines, reporter assays, gene expression analysis, loss-of-function experiments Cell High 12408868
2001 TCF-4 contains distinct binding sites for β-catenin (N-terminal first 50 amino acids) and plakoglobin (residues 51–80); CK2 phosphorylates Tcf-4 at Ser-58/59/60, reducing plakoglobin binding without affecting β-catenin binding; plakoglobin binding to TCF-4 negatively affects TCF-4 transcriptional activity. In vitro kinase assay with CK2, deletion mapping/pulldown, co-immunoprecipitation, ternary complex reconstitution, TCF-4 mutant transcriptional activity assay The Journal of biological chemistry High 11711551
2006 HIC1 antagonizes TCF/β-catenin-mediated transcription by physically associating with TCF-4 and recruiting TCF-4 and β-catenin to HIC1 nuclear bodies, preventing their association with TCF-binding elements of Wnt-responsive genes. Co-immunoprecipitation, nuclear body co-localization imaging, reporter assays (TOPflash), loss-of-function in Wnt-stimulated cells The EMBO journal High 16724116
1999 TCF-4 protein is highly and restrictedly expressed in intestinal crypt epithelium and mammary gland epithelium, with a temporal expression gradient along the crypt-villus axis (high in crypts, low on villi in early fetal intestine), consistent with its role in proliferative compartment maintenance. Immunohistochemistry with TCF-4-specific monoclonal antibodies on mouse and human tissues The American journal of pathology Medium 9916915
1998 TCF-4 binds β-catenin and induces nuclear localization of β-catenin in expressing cells; two isoforms of mouse Tcf-4 are expressed in distinct regions of the embryonic CNS (hindbrain, diencephalon) and limb bud mesenchyme; Tcf-4 expression in the forebrain requires Pax-6. Co-immunoprecipitation of TCF-4 with β-catenin, in situ hybridization, Small eye mutant analysis (epistasis) Mechanisms of development Medium 9784592
2001 TCF-4 acts as a transcriptional repressor of the osteopontin (OPN) promoter; metastasis-inducing DNA containing CAAAG Tcf recognition sequences sequesters endogenous inhibitory TCF-4, thereby de-repressing OPN transcription and promoting metastasis. EMSA with cell extracts, Western blot identification of TCF-4/β-catenin/E-cadherin in DNA complexes, cotransfection of TCF-4 expression vector with OPN promoter-reporter construct, stable transfection, in vivo metastasis assay in syngeneic rats Cancer research High 11454716
2007 Reduced TCF7L2 (Tcf-4) expression in ileal Crohn's disease correlates with decreased α-defensin expression; quantitative binding analysis shows reduced TCF7L2 binding activity at HD-5 and HD-6 promoters in ileal CD biopsies; heterozygous Tcf-4 (+/-) mice show significantly decreased Paneth cell α-defensin levels and bacterial killing activity, establishing Tcf-4 as a causal regulator of Paneth cell α-defensin expression. Quantitative nuclear extract binding assay, murine Tcf-4 heterozygous knockout model, bacterial killing assay, quantitative RT-PCR Journal of immunology High 17709525
2011 TCF7l2 protein is expressed specifically during active remyelination (not developmental myelination) in non-dividing oligodendrocyte precursors; TCF7l2 forms a protein complex with Olig2 but not Olig1 in the context of myelin formation. Co-immunoprecipitation (TCF7l2-Olig2 complex), demyelination/remyelination mouse model (dietary cuprizone), immunofluorescence, Western blot Cellular and molecular neurobiology Medium 22160878
2012 Pancreas-specific deletion of Tcf7l2 impairs glucose-stimulated insulin secretion and GLP-1 response in isolated islets, reduces Glp1r and Ins2 expression, and impairs beta cell mass expansion on high-fat diet, demonstrating a direct role for TCF7L2 in beta cell function. Conditional knockout (Pdx1-Cre × Tcf7l2-flox), glucose tolerance tests, isolated islet insulin secretion assays, optical projection tomography for beta cell mass, quantitative PCR Diabetologia High 22717537
2012 TCF7L2 binds to promoters of gluconeogenic genes (including PEPCK pathway) and inhibits adjacent promoter occupancy by CREB, CRTC2, and FoxO1; hepatic TCF7L2 knockdown increases gluconeogenic gene expression and blood glucose, while overexpression of a nuclear TCF7L2 isoform ameliorates hyperglycemia in high-fat diet mice. ChIP (TCF7L2 binding to gluconeogenic promoters), siRNA knockdown, adenoviral overexpression, CREB/FoxO1 promoter occupancy assay, in vivo glucose tolerance tests PLoS genetics High 23028378
2012 Insulin upregulates hepatic TCF7L2 expression and stimulates β-catenin Ser675 phosphorylation; TCF7L2 knockdown by siRNA increases hepatic glucose production and gluconeogenic gene expression, identifying TCF7L2 as a downstream effector of insulin signaling that represses hepatic gluconeogenesis. siRNA knockdown in hepatocytes, in vivo lithium injection (Wnt activation), TOPGAL transgenic mouse hepatic Wnt activity assay, Western blot for β-catenin Ser675 phosphorylation, glucose production assay American journal of physiology. Endocrinology and metabolism Medium 22967502
2014 TCF7L2 regulates a transcriptional network in pancreatic islets in which ISL1 is a primary direct target; ISL1 in turn regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2, and SLC30A8; the T2D risk allele of rs7903146 is associated with increased TCF7L2 expression and decreased insulin content and secretion. RNA-sequencing of rodent and human islets with TCF7L2 manipulation, human islet gene expression profiles from 66 donors genotyped for rs7903146 Human molecular genetics Medium 25015099
2014 In hepatoma cells, TCF7L2 directly regulates 149 target genes (by ChIP-seq proximal binding) including key regulators of glucose, lipid, and amino acid metabolism; TCF7L2 silencing enhances HNF4α expression and chromatin occupancy, and HNF4α is required for TCF7L2-mediated regulation of a subset of metabolic genes. ChIP-seq (TCF7L2 binding genome-wide), RNA-seq (time-course after Tcf7l2 silencing), co-siRNA epistasis experiments for HNF4α Nucleic acids research High 25414334
2015 Impaired LRP6 activity in LRP6(R611C) mice leads to diminished TCF7L2 activity and increased Sp1-dependent PDGF signaling, promoting loss of VSMC differentiation; Wnt3a administration restores TCF7L2-dependent VSMC differentiation and rescues post-carotid-injury neointima formation. LRP6(R611C) knock-in mouse model, carotid injury model, Wnt3a administration rescue, molecular analysis of PDGF/TCF7L2/Sp1 pathway Cell reports Medium 26489464
2017 Tcf7l2 activity in pancreatic pericytes is required for β-cell function; pericyte-specific Tcf7l2 inactivation impairs glucose tolerance and glucose-stimulated insulin secretion; Tcf7l2-dependent pericytic expression of secreted factors including BMP4 supports β-cell function, and exogenous BMP4 rescues impaired insulin secretion. Pericyte-specific Tcf7l2 conditional knockout mice, glucose tolerance tests, isolated islet GSIS, BMP4 rescue experiment, gene expression analysis Diabetes High 29246974
2017 Alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion at low glucose, reduces alpha cell mass, and increases glucose infusion rates during hypoglycaemic clamp, demonstrating a cell-autonomous role for TCF7L2 in pancreatic alpha cell function and counter-regulatory responses. Alpha cell-selective Tcf7l2 KO (PPGCre × Tcf7l2-flox), hyperinsulinaemic-hypoglycaemic clamp, isolated islet glucagon secretion assay Diabetologia High 28343277
2018 TCF7L2 protein is required for regulation of Wnt signaling during adipogenesis; TCF7L2 expression increases during adipogenesis in 3T3-L1 cells; inactivation of TCF7L2's HMG-box DNA-binding domain in mature adipocytes in vivo leads to whole-body glucose intolerance, hepatic insulin resistance, subcutaneous adipose hypertrophy, and inflammation. In vitro adipogenesis assays (3T3-L1 and primary adipocyte stem cells), adipocyte-specific TCF7L2 HMG-box deletion mouse model, glucose tolerance tests, ChIP-seq and RNA-seq in adipocytes Diabetes High 29317436
2019 Adipocyte-specific deletion of Tcf7l2 leads to adipocyte hypertrophy, impaired glucose tolerance, insulin resistance, reduced triglyceride hydrolase expression, and impaired fasting-induced free fatty acid release; ChIP-seq shows TCF7L2 directly binds and regulates genes involved in lipid and glucose metabolism in adipocytes. Adipocyte-specific Tcf7l2 KO mouse (Adipoq-Cre), high-fat diet challenge, ChIP-seq, RNA-seq, lipolysis assay, glucose/insulin tolerance tests Molecular metabolism High 30948248
2019 MALAT1 enhances TCF7L2 mRNA translation via upregulation of SRSF1 and activation of the mTORC1-4EBP1 axis; MALAT1 increases TCF7L2 mRNA association with heavy polysomes likely through the TCF7L2 5′UTR; knockdown of TCF7L2 abolishes MALAT1's effects on glucose metabolism and tumorigenicity. Polysome fractionation, 5′UTR-reporter assays, pharmacological/genetic mTOR inhibition, hypophosphorylated 4EBP1 mutant expression, siRNA knockdown Cancer research Medium 30914432
2019 TCF7L2 is densely expressed in the medial habenula (mHb) and regulates nicotinic acetylcholine receptor function there; inhibition of TCF7L2 signaling in the mHb increases nicotine intake; nicotine increases blood glucose via TCF7L2-dependent stimulation of the mHb; virus tracing identifies a polysynaptic mHb-to-pancreas connection; mutant Tcf7l2 rats are resistant to nicotine-induced blood glucose dysregulation. Viral TCF7L2 inhibition in the mHb, nicotine self-administration assay, anterograde/retrograde viral tracing, Tcf7l2 mutant rat model, blood glucose and glucagon/insulin measurements Nature High 31619789
2020 TCF7L2 regulates postmitotic differentiation programmes in the thalamus, functioning as a thalamic terminal selector; loss of Tcf7l2 disrupts thalamo-habenular connectivity, regional transcription factor expression, cell migration/axon guidance genes, and impairs terminal electrophysiological features (firing modes) of thalamic neurons; many of these genes are direct TCF7L2 targets. Complete and conditional Tcf7l2 knockout mice, postnatal Tcf7l2 KO, electrophysiology, ChIP for direct target identification, RNA-seq Development (Cambridge, England) High 32675279
2021 TCF7L2 directly represses BMP4 transcription by binding to the Bmp4 gene regulatory element in oligodendrocytes; disruption of TCF7l2 in mice causes oligodendroglial BMP4 upregulation and canonical BMP4 signaling activation; enforced TCF7l2 expression promotes oligodendrocyte differentiation by reducing autocrine BMP4 secretion; compound genetic deletion of oligodendroglial BMP4 rescues arrested OL differentiation caused by TCF7l2 disruption. Tcf7l2 conditional KO in oligodendrocytes, BMP4 conditional KO (compound genetics/epistasis), ChIP (TCF7l2 binding to Bmp4 regulatory element), in vitro OL differentiation assays The Journal of neuroscience High 33452226
2016 TCF7L2 mediates thalamic-specific nuclear translocation of β-catenin in response to lithium; silencing Tcf7l2 in thalamic neurons prevents β-catenin from entering the nucleus even under lithium treatment; ectopic Tcf7l2 expression in cortical neurons shifts β-catenin to the nucleus; Tcf7l2 knockdown in zebrafish abolishes lithium's behavioral effects. Lentiviral Tcf7l2 silencing in thalamic neurons, ectopic Tcf7l2 expression in cortical neurons, nuclear fractionation, immunofluorescence, zebrafish tcf7l2 knockdown behavioral assay Neuropharmacology Medium 27793772
2023 TCF7L2 is the dominant Wnt effector in postnatal astrocytes; conditional Tcf7l2 KO in postnatal astrocytes enlarges astrocytes, disrupts tiling and gap junction coupling, increases cortical excitatory and inhibitory synapse numbers, and increases adult social interaction, demonstrating a cell-autonomous role for TCF7L2-dependent Wnt/β-catenin signaling in astrocyte maturation and synapse number restriction. Postnatal astrocyte-specific Tcf7l2 conditional KO mice, astrocyte morphology and tiling analysis, gap junction coupling assay, synapse quantification, behavioral testing Molecular psychiatry High 37798419
2005 TIS7 downregulates β-catenin/TCF-4 transcriptional activity through interaction with histone deacetylase-containing complexes; TIS7 overexpression leads to β-catenin interaction with enzymatically active histone deacetylases; TIS7 homologous deletion in mouse embryonic fibroblasts increases TOPflash reporter activity and expression of c-Myc and OPN. TOPflash reporter assay, co-immunoprecipitation with histone deacetylases, TIS7 knockout MEFs, TIS7 overexpression, gene expression analysis The Journal of biological chemistry Medium 16204248
2011 TCF7L2 splice variants have distinct effects on β-cell survival and function: clone B1 (lacking exons 13–16) induces β-cell apoptosis, impairs function, and inhibits Wnt signaling, while clones B3 and B7 (containing exon 13) improve β-cell survival and function and activate Wnt signaling; TCF7L2 depletion activates GSK3β independently of ER stress. TCF7L2 splice variant overexpression and knockdown in human isolated islets, apoptosis assays, GSIS, TOPflash/FOPflash reporter assay, GSK3β activity measurement Human molecular genetics Medium 21357677
2012 TCF7L2 overexpression in isolated exocrine cells induces duct cell proliferation and islet-like cell cluster (ICC) formation in a JAK2/STAT3-dependent manner, suggesting a role for TCF7L2 in beta cell regeneration from ductal epithelium. Adenoviral TCF7L2 overexpression in isolated exocrine cells, JAK2/STAT3 pathway inhibition, quantification of ICC formation, in vivo high-fat diet and streptozotocin mouse models Diabetologia Medium 22945304
2018 TCF7L2 binds directly to the PIK3R1 promoter at evolutionarily conserved TCF7L2-binding motifs and inhibits PIK3R1/PI3K p85 expression, thereby activating PI3K/AKT signaling and stimulating insulin secretion in pancreatic β-cells. ChIP-PCR, luciferase reporter assay, lentiviral TCF7L2 knockdown/overexpression, Western blot for PI3K p85 and p-AKT, ELISA for insulin secretion Diabetology & metabolic syndrome Medium 31312258
2018 TCF7L2 and EGR1 synergistically activate LCN2 transcription by directly binding to their respective sites within the LCN2 promoter (-273/-209 for TCF7L2; -710/-616 for EGR1) via the ERK signaling pathway; recombinant LCN2 further enhances ERK activation and TCF7L2/EGR1 expression in a positive feedback loop. ChIP, luciferase reporter with deletion mapping, MEK inhibitor (U0126) epistasis, overexpression and knockdown, migration/invasion assays Cellular signalling Medium 30557604
2022 In a Huntington's disease mouse model, TCF7L2-dependent transcription is repressed; in vivo Tcf7l2 overexpression restores myelin gene expression and remyelination in demyelinated R6/2 mice, causally linking impaired TCF7L2-dependent transcription to poor myelination in HD. RNA-sequencing of HD mouse callosal white matter and OPCs, proteomic analysis, in vivo Tcf7l2 overexpression (viral vector) in R6/2 mice, cuprizone demyelination/remyelination assay Cell reports Medium 36044851
2021 Upregulation of TCF7L2 in vascular smooth muscle cells is associated with BCL2 repression and promotes VSMC apoptosis, which is a potential driver of thoracic aortic aneurysm; the TAA genetic association at the TCF7L2 locus colocalizes with an aortic eQTL of TCF7L2. In vitro TCF7L2 upregulation experiment in VSMCs, BCL2 expression assay, eQTL colocalization analysis American journal of human genetics Low 34265237
2020 Adipocyte-specific Tcf7l2 deletion leads to impaired glucose tolerance, increased fat mass, reduced incretin (GLP-1 and GIP) levels, and increased circulating NEFA and FABP4, with a sexually dimorphic phenotype (males only), suggesting TCF7L2 in adipocytes regulates pancreatic islet and enteroendocrine cell function via paracrine/endocrine mechanisms. Adipoq-Cre × Tcf7l2-flox conditional KO mice, normal chow and high-fat diet challenge, in vitro GSIS, incretin measurements, NEFA and FABP4 plasma assays Diabetologia Medium 33068125

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 1703 12408868
2007 TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. Journal of molecular medicine (Berlin, Germany) 281 17476472
2007 The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. Journal of immunology (Baltimore, Md. : 1950) 230 17709525
2001 The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate beta-catenin/TCF-4 signaling. Oncogene 174 11313997
2022 Interaction of lncRNA MIR100HG with hnRNPA2B1 facilitates m6A-dependent stabilization of TCF7L2 mRNA and colorectal cancer progression. Molecular cancer 156 35279145
2014 TCF7L2 is a master regulator of insulin production and processing. Human molecular genetics 152 25015099
2019 Long Noncoding RNA MALAT1 Regulates Cancer Glucose Metabolism by Enhancing mTOR-Mediated Translation of TCF7L2. Cancer research 148 30914432
2007 Downregulation of Dkk3 activates beta-catenin/TCF-4 signaling in lung cancer. Carcinogenesis 142 18048388
2008 The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus. Molecular endocrinology (Baltimore, Md.) 137 18599616
1999 Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium. The American journal of pathology 131 9916915
2021 The Role of TCF7L2 in Type 2 Diabetes. Diabetes 130 34016596
2007 TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population. Diabetes 129 17416797
2018 The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte Development and Function. Diabetes 103 29317436
2001 The transcriptional factor Tcf-4 contains different binding sites for beta-catenin and plakoglobin. The Journal of biological chemistry 102 11711551
2019 Habenular TCF7L2 links nicotine addiction to diabetes. Nature 94 31619789
2006 Repressor roles for TCF-4 and Sfrp1 in Wnt signaling in breast cancer. Oncogene 90 16532032
2016 Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis. Endocrine reviews 87 27159876
1998 TCF-4 binds beta-catenin and is expressed in distinct regions of the embryonic brain and limbs. Mechanisms of development 87 9784592
2012 Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice. Diabetologia 85 22717537
2009 Tissue-specific alternative splicing of TCF7L2. Human molecular genetics 83 19602480
2007 The new type 2 diabetes gene TCF7L2. Current opinion in clinical nutrition and metabolic care 83 17563454
2022 TCF7L2 promotes anoikis resistance and metastasis of gastric cancer by transcriptionally activating PLAUR. International journal of biological sciences 82 35864968
2019 Wnt/β-catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind. FEBS letters 80 31218672
2006 HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies. The EMBO journal 80 16724116
2012 TCF7L2 modulates glucose homeostasis by regulating CREB- and FoxO1-dependent transcriptional pathway in the liver. PLoS genetics 71 23028378
2019 Targeted deletion of Tcf7l2 in adipocytes promotes adipocyte hypertrophy and impaired glucose metabolism. Molecular metabolism 69 30948248
2012 SPINDLIN1 promotes cancer cell proliferation through activation of WNT/TCF-4 signaling. Molecular cancer research : MCR 65 22258766
2012 The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis. American journal of physiology. Endocrinology and metabolism 64 22967502
2012 MiR-24 regulates the proliferation and invasion of glioma by ST7L via β-catenin/Tcf-4 signaling. Cancer letters 64 23142218
2015 Impaired LRP6-TCF7L2 Activity Enhances Smooth Muscle Cell Plasticity and Causes Coronary Artery Disease. Cell reports 62 26489464
2013 TCTP promotes glioma cell proliferation in vitro and in vivo via enhanced β-catenin/TCF-4 transcription. Neuro-oncology 61 24311645
2019 TCF-4 Regulated lncRNA-XIST Promotes M2 Polarization Of Macrophages And Is Associated With Lung Cancer. OncoTargets and therapy 60 31632059
2011 TCF7L2 splice variants have distinct effects on beta-cell turnover and function. Human molecular genetics 57 21357677
2001 Metastasis-inducing dna regulates the expression of the osteopontin gene by binding the transcription factor Tcf-4. Cancer research 55 11454716
2008 TCF7L2 genetic defect and type 2 diabetes. Current diabetes reports 54 18445358
2015 Geniposide promotes beta-cell regeneration and survival through regulating β-catenin/TCF7L2 pathway. Cell death & disease 53 25950476
2020 The β-catenin/TCF-4-LINC01278-miR-1258-Smad2/3 axis promotes hepatocellular carcinoma metastasis. Oncogene 51 32372060
2019 LncRNA SPRY4-IT1 regulates breast cancer cell stemness through competitively binding miR-6882-3p with TCF7L2. Journal of cellular and molecular medicine 50 31736268
2019 KIFC1 is activated by TCF-4 and promotes hepatocellular carcinoma pathogenesis by regulating HMGA1 transcriptional activity. Journal of experimental & clinical cancer research : CR 47 31340839
2010 Molecular function of TCF7L2: Consequences of TCF7L2 splicing for molecular function and risk for type 2 diabetes. Current diabetes reports 45 20878273
2017 Pancreatic Pericytes Support β-Cell Function in a Tcf7l2-Dependent Manner. Diabetes 44 29246974
2015 IKKβ Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis. Cancer research 44 25744721
2015 TCF7L2 Genotype and α-Cell Function in Humans Without Diabetes. Diabetes 44 26525881
2014 Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin. Diabetologia 43 24906949
2010 Pleiotropic effects of TCF7L2 gene variants and its modulation in the metabolic syndrome: from the LIPGENE study. Atherosclerosis 43 21115178
2007 Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors. Gastroenterology 43 17920061
2023 VE-Cadherin modulates β-catenin/TCF-4 to enhance Vasculogenic Mimicry. Cell death & disease 42 36797281
2014 The mechanisms of genome-wide target gene regulation by TCF7L2 in liver cells. Nucleic acids research 42 25414334
2011 Wnt-β-catenin-Tcf-4 signalling-modulated invasiveness is dependent on osteopontin expression in breast cancer. British journal of cancer 40 21772333
2021 EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2. Cell death & disease 39 33712565
2016 microRNA-328 inhibits cervical cancer cell proliferation and tumorigenesis by targeting TCF7L2. Biochemical and biophysical research communications 39 27181358
2011 β-catenin/Tcf-4 complex transcriptionally regulates AKT1 in glioma. International journal of oncology 39 21720709
2007 Overexpression of axin downregulates TCF-4 and inhibits the development of lung cancer. Annals of surgical oncology 39 17768662
2021 Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm. American journal of human genetics 38 34265237
2021 The broad pathogenetic role of TCF7L2 in human diseases beyond type 2 diabetes. Journal of cellular physiology 36 34612510
2012 TCF7L2 promotes beta cell regeneration in human and mouse pancreas. Diabetologia 36 22945304
2020 TCF7L2 regulates postmitotic differentiation programmes and excitability patterns in the thalamus. Development (Cambridge, England) 35 32675279
2020 Circ-PRMT5 promotes breast cancer by the miR-509-3p/TCF7L2 axis activating the PI3K/AKT pathway. The journal of gene medicine 35 33277756
2018 Tcf7L2 is essential for neurogenesis in the developing mouse neocortex. Neural development 34 29751817
2018 RUNX3 inhibits glioma survival and invasion via suppression of the β-catenin/TCF-4 signaling pathway. Journal of neuro-oncology 34 29916101
2011 Tcf7l2 is tightly controlled during myelin formation. Cellular and molecular neurobiology 34 22160878
2023 Astrocytic β-catenin signaling via TCF7L2 regulates synapse development and social behavior. Molecular psychiatry 33 37798419
2009 Alternative splicing of TCF7L2 gene in omental and subcutaneous adipose tissue and risk of type 2 diabetes. PloS one 33 19789636
2021 The Wnt Effector TCF7l2 Promotes Oligodendroglial Differentiation by Repressing Autocrine BMP4-Mediated Signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 33452226
2016 MiR-181a-5p regulates 3T3-L1 cell adipogenesis by targeting Smad7 and Tcf7l2. Acta biochimica et biophysica Sinica 32 27742678
2013 Reg4-induced mitogenesis involves Akt-GSK3β-β-Catenin-TCF-4 signaling in human colorectal cancer. Molecular carcinogenesis 32 24151146
2016 Transcription Factor 7-Like 2 (TCF7L2) rs7903146 Polymorphism as a Risk Factor for Gestational Diabetes Mellitus: A Meta-Analysis. PloS one 31 27058589
2005 TIS7 regulation of the beta-catenin/Tcf-4 target gene osteopontin (OPN) is histone deacetylase-dependent. The Journal of biological chemistry 29 16204248
2012 Inhibition of Tcf-4 induces apoptosis and enhances chemosensitivity of colon cancer cells. PloS one 28 23029137
2020 Adipocyte-specific deletion of Tcf7l2 induces dysregulated lipid metabolism and impairs glucose tolerance in mice. Diabetologia 27 33068125
2017 Association between TCF7L2 polymorphisms and gestational diabetes mellitus: A meta-analysis. Journal of diabetes investigation 26 28002648
2020 Artesunate inhibits atherosclerosis by upregulating vascular smooth muscle cells-derived LPL expression via the KLF2/NRF2/TCF7L2 pathway. European journal of pharmacology 25 32739175
2022 TCF7l2, a nuclear marker that labels premyelinating oligodendrocytes and promotes oligodendroglial lineage progression. Glia 24 35841271
2021 Transcription Factor-7-Like-2 (TCF7L2) in Atherosclerosis: A Potential Biomarker and Therapeutic Target. Frontiers in cardiovascular medicine 24 34568447
2016 Gastrin promotes the metastasis of gastric carcinoma through the β-catenin/TCF-4 pathway. Oncology reports 24 27430592
2013 Limited TCF7L2 expression in MS lesions. PloS one 24 23977356
2009 Expression of the diabetes-associated gene TCF7L2 in adult mouse brain. The Journal of comparative neurology 24 19845015
2021 TCF7L2 lncRNA: a link between bipolar disorder and body mass index through glucocorticoid signaling. Molecular psychiatry 23 34535768
2019 TCF7L2 regulates pancreatic β-cell function through PI3K/AKT signal pathway. Diabetology & metabolic syndrome 23 31312258
2013 Association between TCF7L2 gene polymorphism and cancer risk: a meta-analysis. PloS one 23 23951231
2022 A TCF7L2-responsive suppression of both homeostatic and compensatory remyelination in Huntington disease mice. Cell reports 21 36044851
2015 Polymorphisms in FTO and TCF7L2 genes of Euro-Brazilian women with gestational diabetes. Clinical biochemistry 21 26102344
2013 Association of rs12255372 in the TCF7L2 gene with type 2 diabetes mellitus: a meta-analysis. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 20 23579632
2018 TCF7L2 correlation in both insulin secretion and postprandial insulin sensitivity. Diabetology & metabolic syndrome 19 29736187
2017 Investigation of TCF7L2, LEP and LEPR polymorphisms with esophageal squamous cell carcinomas. Oncotarget 19 29312594
2010 En2, Pax2/5 and Tcf-4 transcription factors cooperate in patterning the Xenopus brain. Developmental biology 19 20171202
2004 Differential expression and splicing isoform analysis of human Tcf-4 transcription factor in brain tumors. International journal of oncology 19 15547706
2022 MicroRNA-22-3p targeted regulating transcription factor 7-like 2 (TCF7L2) constrains the Wnt/β-catenin pathway and malignant behavior in osteosarcoma. Bioengineered 18 34753394
2019 A meta-analysis on associations of FTO, MTHFR and TCF7L2 polymorphisms with polycystic ovary syndrome. Genomics 18 31470081
2017 Cumulative evidence for relationships between multiple variants in the VTI1A and TCF7L2 genes and cancer incidence. International journal of cancer 18 28949031
2018 TCF7L2 and EGR1 synergistic activation of transcription of LCN2 via an ERK1/2-dependent pathway in esophageal squamous cell carcinoma cells. Cellular signalling 17 30557604
2016 Polymorphisms in TCF7L2 gene are associated with gestational diabetes mellitus in Chinese Han population. Scientific reports 17 27465520
2016 Common variants in TCF7L2 and CDKAL1 genes and risk of type 2 diabetes mellitus in Egyptians. Journal, genetic engineering & biotechnology 17 30647622
2007 The TCF7L2 locus and type 1 diabetes. BMC medical genetics 17 17683561
2024 HIF2α Promotes Cancer Metastasis through TCF7L2-Dependent Fatty Acid Synthesis in ccRCC. Research (Washington, D.C.) 16 38390305
2022 TCF7L2 promotes ER stress signaling in diabetic retinopathy. Experimental eye research 16 35691375
2017 Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice. Diabetologia 16 28343277
2016 TCF7L2 involvement in estradiol- and progesterone-modulated islet and hepatic glucose homeostasis. Scientific reports 16 27108846
2016 TCF7L2 mediates the cellular and behavioral response to chronic lithium treatment in animal models. Neuropharmacology 16 27793772
2018 ADIPOQ, KCNJ11 and TCF7L2 polymorphisms in type 2 diabetes in Kyrgyz population: A case-control study. Journal of cellular and molecular medicine 15 30467975

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