TCF7L2

Transcription factor 7-like 2 (T-cell specific, HMG-box)
PDB rendering based on 1jdh.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1JDH​, 1JPW​, 2GL7​
Identifiers
Symbols	TCF7L2 ; TCF-4; TCF4
External IDs	OMIM: 602228 MGI: 1202879 HomoloGene: 7564 GeneCards: TCF7L2 Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding • RNA polymerase II core promoter sequence-specific DNA binding • RNA polymerase II repressing transcription factor binding • chromatin binding • transcription factor activity, sequence-specific DNA binding • protein binding • beta-catenin binding • transcription factor binding • protein kinase binding • nuclear hormone receptor binding • sequence-specific DNA binding • transcription regulatory region DNA binding • gamma-catenin binding • armadillo repeat domain binding Cellular component • nuclear chromatin • nucleus • nucleoplasm • transcription factor complex • cytoplasm • PML body • protein-DNA complex • beta-catenin-TCF7L2 complex Biological process • negative regulation of transcription from RNA polymerase II promoter • blood vessel development • cellular glucose homeostasis • glycogen metabolic process • glucose metabolic process • transcription, DNA-templated • regulation of transcription from RNA polymerase II promoter • cell cycle arrest • cell proliferation • cellular response to starvation • response to glucose • post-embryonic development • positive regulation of triglyceride biosynthetic process • positive regulation of heparan sulfate proteoglycan biosynthetic process • oligodendrocyte development • neural tube development • pituitary gland development • bone mineralization • negative regulation of BMP signaling pathway • embryonic genitalia morphogenesis • pancreas development • regulation of myelination • positive regulation of insulin secretion • positive regulation of protein binding • secretory granule localization • regulation of hormone metabolic process • somatic stem cell maintenance • multicellular organism growth • catenin import into nucleus • regulation of gluconeogenesis by regulation of transcription from RNA polymerase II promoter • negative regulation of fibroblast growth factor receptor signaling pathway • odontogenesis of dentin-containing tooth • glucose homeostasis • positive regulation of apoptotic process • negative regulation of sequence-specific DNA binding transcription factor activity • maintenance of DNA repeat elements • skin development • canonical Wnt signaling pathway involved in positive regulation of epithelial to mesenchymal transition • fat cell differentiation • negative regulation of fat cell differentiation • positive regulation of gluconeogenesis • negative regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • negative regulation of organ growth • positive regulation of protein export from nucleus • embryonic digestive tract morphogenesis • embryonic hindgut morphogenesis • myoblast fate commitment • regulation of skeletal muscle tissue development • regulation of smooth muscle cell proliferation • generation of neurons • regulation of oligodendrocyte differentiation • positive regulation of epithelial cell proliferation • positive regulation of protein kinase B signaling • canonical Wnt signaling pathway • face morphogenesis • regulation of insulin secretion involved in cellular response to glucose stimulus • negative regulation of canonical Wnt signaling pathway • insulin metabolic process • negative regulation of type B pancreatic cell apoptotic process • negative regulation of extrinsic apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6934	21416
Ensembl	ENSG00000148737	ENSMUSG00000024985
UniProt	Q9NQB0	Q924A0
RefSeq (mRNA)	NM_001146274	NM_001142918
RefSeq (protein)	NP_001139746	NP_001136390
Location (UCSC)	Chr 10: 112.95 – 113.17 Mb	Chr 19: 55.74 – 55.93 Mb
PubMed search

Transcription factor 7-like 2 (T-cell specific, HMG-box) also known as TCF7L2 or TCF4 is a protein acting as a transcription factor. In humans this protein is encoded by the TCF7L2 gene.^[1][2] The single nucleotide polymorphism (SNP) within the TCF7L2 gene, rs7903146, is, to date, the most significant genetic marker^[3] associated with Type 2 diabetes mellitus (T2DM) risk. SNPs in this gene are linked to higher risk to develop type 2 diabetes,^[4] as well as gestational diabetes.^[5]

Structure of complex between TCF7L2 (orange), β-catenin (red), and BCL9 (brown).^[6]

Function

TCF7L2 is a transcription factor influencing the transcription of several genes thereby exerting a large variety of functions within the cell. It is a member of the Wnt signaling pathway. Stimulation of the pathway leads to the association of β-catenin with BCL9, translocation to the nucleus, and association with TCF7L2,^[7] which in turn results in the activation of Wnt target genes, specifically repressing proglucagon synthesis in enteroendocrine cells.^[4][8]

Clinical significance

TCF7L2 is implicated in a large variety of diseases. Several single nucleotide polymorphisms are associated with type 2 diabetes. In European populations it was found to be a major determinant of type 2 risk.^[4]

A frameshift mutation of TCF7L2 is implicated in colorectal cancer.^[9][10] Variants of the gene are most likely involved in many other cancer types.^[11]

Model organisms

Model organisms have been used in the study of TCF7L2 function. A conditional knockout mouse line called Tcf7l2^{tm1a(EUCOMM)Wtsi} was generated at the Wellcome Trust Sanger Institute.^[12] Male and female animals underwent a standardized phenotypic screen^[13] to determine the effects of deletion.^{[14][15][16][17]} Additional screens performed: - In-depth immunological phenotyping^[18]

Tcf7l2 knockout mouse phenotype

Characteristic	Phenotype
All data available at.[13][18]
Insulin	Normal
Homozygous viability at P14	Abnormal
Recessive lethal study	Abnormal
Body weight	Normal
Neurological assessment	Normal
Grip strength	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Abnormal
Radiography	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology 16 Weeks	Normal
Peripheral blood leukocytes 16 Weeks	Normal
Epidermal Immune Composition	Normal
Influenza Challenge	Normal

Nomenclature

While TCF4 is sometimes misleadingly used as an alias symbol for TCF7L2, it is also the symbol officially approved by the HUGO Gene Nomenclature Committee for the transcription factor 4 gene.

See also

• TCF/LEF family

References

1. "Entrez Gene: TCF7L2".
2. Castrop J, van Norren K, Clevers H (1992). "A gene family of HMG-box transcription factors with homology to TCF-1". Nucleic Acids Res. 20 (3): 611. doi:10.1093/nar/20.3.611. PMC 310434. PMID 1741298.
3. Vaquero AR, Ferreira NE, Omae SV, Rodrigues MV, Teixeira SK, Krieger JE, Pereira AC (2012). "Using gene-network landscape to dissect genotype effects of TCF7L2 genetic variant on diabetes and cardiovascular risk". Physiol. Genomics 44 (19): 903–14. doi:10.1152/physiolgenomics.00030.2012. PMID 22872755.
4. Jin T, Liu L (2008). "The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus". Mol. Endocrinol. 22 (11): 2383–92. doi:10.1210/me.2008-0135. PMID 18599616.
5. Zhang C, Bao W, Rong Y, Yang H, Bowers K, Yeung E, Kiely M (2013). "Genetic variants and the risk of gestational diabetes mellitus: a systematic review". Hum. Reprod. Update 19 (4): 376–90. doi:10.1093/humupd/dmt013. PMID 23690305.
6. PDB: 2GL7​; Sampietro J, Dahlberg CL, Cho US, Hinds TR, Kimelman D, Xu W (October 2006). "Crystal structure of a beta-catenin/BCL9/Tcf4 complex". Mol. Cell 24 (2): 293–300. doi:10.1016/j.molcel.2006.09.001. PMID 17052462.
7. Lee JM, Dedhar S, Kalluri R, Thompson EW (2006). "The epithelial-mesenchymal transition: new insights in signaling, development, and disease". J. Cell Biol. 172 (7): 973–81. doi:10.1083/jcb.200601018. PMC 2063755. PMID 16567498.
8. Online 'Mendelian Inheritance in Man' (OMIM) 602228
9. Slattery ML, Folsom AR, Wolff R, Herrick J, Caan BJ, Potter JD (2008). "Transcription factor 7-like 2 polymorphism and colon cancer". Cancer Epidemiol. Biomarkers Prev. 17 (4): 978–82. doi:10.1158/1055-9965.EPI-07-2687. PMC 2587179. PMID 18398040.
10. Hazra A, Fuchs CS, Chan AT, Giovannucci EL, Hunter DJ (2008). "Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk". Cancer Causes Control 19 (9): 975–80. doi:10.1007/s10552-008-9164-3. PMC 2719293. PMID 18478343.
11. Tang W, Dodge M, Gundapaneni D, Michnoff C, Roth M, Lum L (2008). "A genome-wide RNAi screen for Wnt/beta-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer". Proc. Natl. Acad. Sci. U.S.A. 105 (28): 9697–702. Bibcode:2008PNAS..105.9697T. doi:10.1073/pnas.0804709105. PMC 2453074. PMID 18621708.
12. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
13. "International Mouse Phenotyping Consortium".
14. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
15. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
16. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
17. White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
18. "Infection and Immunity Immunophenotyping (3i) Consortium".

Further reading

• Segditsas S, Tomlinson I (2006). "Colorectal cancer and genetic alterations in the Wnt pathway". Oncogene 25 (57): 7531–7. doi:10.1038/sj.onc.1210059. PMID 17143297.
• Florez JC (2007). "The new type 2 diabetes gene TCF7L2". Curr Opin Clin Nutr Metab Care 10 (4): 391–6. doi:10.1097/MCO.0b013e3281e2c9be. PMID 17563454.
• Castrop J, van Norren K, Clevers H (1992). "A gene family of HMG-box transcription factors with homology to TCF-1". Nucleic Acids Res. 20 (3): 611. doi:10.1093/nar/20.3.611. PMC 310434. PMID 1741298.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Korinek V, et al. (1997). "Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma". Science 275 (5307): 1784–7. doi:10.1126/science.275.5307.1784. PMID 9065401.
• Suzuki Y, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• He TC, et al. (1998). "Identification of c-MYC as a target of the APC pathway". Science 281 (5382): 1509–12. Bibcode:1998Sci...281.1509H. doi:10.1126/science.281.5382.1509. PMID 9727977.
• Barker N, Huls G, Korinek V, Clevers H (1999). "Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium". Am. J. Pathol. 154 (1): 29–35. doi:10.1016/S0002-9440(10)65247-9. PMC 1853446. PMID 9916915.
• Omer CA, Miller PJ, Diehl RE, Kral AM (1999). "Identification of Tcf4 residues involved in high-affinity beta-catenin binding". Biochem. Biophys. Res. Commun. 256 (3): 584–90. doi:10.1006/bbrc.1999.0379. PMID 10080941.
• Giannini AL, Vivanco MM, Kypta RM (2000). "Analysis of beta-catenin aggregation and localization using GFP fusion proteins: nuclear import of alpha-catenin by the beta-catenin/Tcf complex". Exp. Cell Res. 255 (2): 207–20. doi:10.1006/excr.1999.4785. PMID 10694436.
• Duval A, Busson-Leconiat M, Berger R, Hamelin R (2000). "Assignment of the TCF-4 gene (TCF7L2) to human chromosome band 10q25.3". Cytogenet. Cell Genet. 88 (3-4): 264–5. doi:10.1159/000015534. PMID 10828605.
• Duval A, et al. (2000). "The human T-cell transcription factor-4 gene: structure, extensive characterization of alternative splicings, and mutational analysis in colorectal cancer cell lines". Cancer Res. 60 (14): 3872–9. PMID 10919662.
• Brantjes H, Roose J, van De Wetering M, Clevers H (2001). "All Tcf HMG box transcription factors interact with Groucho-related co-repressors". Nucleic Acids Res. 29 (7): 1410–9. doi:10.1093/nar/29.7.1410. PMC 31284. PMID 11266540.
• Palacino JJ, et al. (2001). "Presenilin 1 regulates beta-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion". J. Biol. Chem. 276 (42): 38563–9. doi:10.1074/jbc.M105376200. PMID 11504726.
• Miravet S, et al. (2002). "The transcriptional factor Tcf-4 contains different binding sites for beta-catenin and plakoglobin". J. Biol. Chem. 277 (3): 1884–91. doi:10.1074/jbc.M110248200. PMID 11711551.
• Graham TA, et al. (2001). "Tcf4 can specifically recognize beta-catenin using alternative conformations". Nat. Struct. Biol. 8 (12): 1048–52. doi:10.1038/nsb718. PMID 11713475.
• Poy F, Lepourcelet M, Shivdasani RA, Eck MJ (2001). "Structure of a human Tcf4-beta-catenin complex". Nat. Struct. Biol. 8 (12): 1053–7. doi:10.1038/nsb720. PMID 11713476.
• Thiele A, et al. (2001). "Regulation and possible function of beta-catenin in human monocytes". J. Immunol. 167 (12): 6786–93. doi:10.4049/jimmunol.167.12.6786. PMID 11739494.
• Marchenko GN, Marchenko ND, Leng J, Strongin AY (2002). "Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin". Biochem. J. 363 (Pt 2): 253–62. doi:10.1042/0264-6021:3630253. PMC 1222473. PMID 11931652.
• Leung JY, et al. (2002). "Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling". J. Biol. Chem. 277 (24): 21657–65. doi:10.1074/jbc.M200139200. PMID 11940574.

External links

• TCF7L2 here called TCF4 features on this Wnt pathway web site: Wnt signalling molecules TCFs
• Structure determination of TCF7L2: PDB entry 2GL7 and related publication on PubMed
• PubMed GeneRIFs (summaries of related scientific publications) -
• Weizmann Institute GeneCard for TCF7L2