Biology:TCF7L2

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Transcription factor 7-like 2 (T-cell specific, HMG-box), also known as TCF7L2 or TCF4, is a protein acting as a transcription factor that, in humans, is encoded by the TCF7L2 gene.[1][2] The TCF7L2 gene is located on chromosome 10q25.2–q25.3, contains 19 exons.[3][4] As a member of the TCF family, TCF7L2 can form a bipartite transcription factor and influence several biological pathways, including the Wnt signalling pathway.[5]

Single-nucleotide polymorphisms (SNPs) in this gene are especially known to be linked to higher risk to develop type 2 diabetes,[5] gestational diabetes,[6] multiple neurodevelopmental disorders[7][8] including schizophrenia[9][10] and autism spectrum disorder,[11][12] as well as other diseases.[13][14] The SNP rs7903146, within the TCF7L2 gene, is, to date, the most significant genetic marker associated with type 2 diabetes risk.[15]

Structure of complex between TCF7L2 (orange), β-catenin (red), and BCL9 (brown)[16]

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 TCF family that can form a bipartite transcription factor (β-catenin/TCF) alongside β-catenin.[5] Bipartite transcription factors can have large effects on the Wnt signalling pathway.[5] Stimulation of the Wnt signaling pathway leads to the association of β-catenin with BCL9, translocation to the nucleus, and association with TCF7L2,[17] which in turn results in the activation of Wnt target genes. The activation of the Wnt target genes specifically represses proglucagon synthesis in enteroendocrine cells.[5][4] The repression of TCF7L2 using HMG-box repressor (HBP1) inhibits Wnt signalling.[5] Therefore, TCF7L2 is an effector in the Wnt signalling pathway. TCF7L2's role in glucose metabolism is expressed in many tissues such as gut, brain, liver, and skeletal muscle. However, TCF7L2 does not directly regulate glucose metabolism in β-cells, but regulates glucose metabolism in pancreatic and liver tissues.[18] That said, TCF7L2 directly regulates the expression of multiple transcription factors, axon guidance cues, cell adhesion molecules and ion channels in the thalamus.[19]

The TCF7L2 gene encoding the TCF7L2 transcription factor, exhibits multiple functions through its polymorphisms and thus, is known as a pleiotropic gene. Type 2 diabetes T2DM susceptibility is exhibited in carriers of TCF7L2 rs7903146C>T[20][21] and rs290481T>C[21] polymorphisms.[20][21] TCF7L2 rs290481T>C polymorphism, however, has shown no significant correlation to the susceptibility to gestational diabetes mellitus (GDM) in a Chinese Han population, whereas the T alleles of rs7903146[21] and rs1799884[6] increase susceptibility to GDM in the Chinese Han population.[21][6] The difference in effects of the different polymorphisms of the gene indicate that the gene is indeed pleiotropic.

Structure

The TCF7L2 gene, encoding the TCF7L2 protein, is located on chromosome 10q25.2-q25.3. The gene contains 19 exons.[3][4] Of the 19 exons, 5 are alternative.[4] The TCF7L2 protein contains 619 amino acids and its molecular mass is 67919 Da.[22] TCF7L2's secondary structure is a helix-turn-helix structure.[23]

Tissue distribution

TCF7L2 is primarily expressed in brain (mainly in the diencephalon, including especially high in the thalamus[19][24][25]), liver, intestine and fat cells. It does not primarily operate in the β-cells in the pancreas.[26]

Clinical significance

Type 2 Diabetes

Several single nucleotide polymorphisms within the TCF7L2 gene have been associated with type 2 diabetes. Studies conducted by Ravindranath Duggirala and Michael Stern at The University of Texas Health Science Center at San Antonio were the first to identify strong linkage for type 2 diabetes at a region on Chromosome 10 in Mexican Americans [27] This signal was later refined by Struan Grant and colleagues at DeCODE genetics and isolated to the TCF7L2 gene.[28] The molecular and physiological mechanisms underlying the association of TCF7L2 with type 2 diabetes are under active investigation, but it is likely that TCF7L2 has important biological roles in multiple metabolic tissues, including the pancreas, liver and adipose tissue.[26][29] TCF7L2 polymorphisms can increase susceptibility to type 2 diabetes by decreasing the production of glucagon-like peptide-1 (GLP-1).[5]

Gestational Diabetes (GDM)

TCF7L2 modulates pancreatic islet β-cell function strongly implicating its significant association with GDM risk.[6] T alleles of rs7903146[21] and rs1799884[6] TCF7L2 polymorphisms increase susceptibility to GDM in the Chinese Han population.[21][6]

Cancer

TCF7L2 plays a role in colorectal cancer.[13] A frameshift mutation of TCF7L2 provided evidence that TCF7L2 is implicated in colorectal cancer.[30][31] The silencing of TCF7L2 in KM12 colorectal cancer cells provided evidence that TCF7L2 played a role in proliferation and metastasis of cancer cells in colorectal cancer.[13]

Variants of the gene are most likely involved in many other cancer types.[32] TCF7L2 is indirectly involved in prostate cancer through its role in activating the PI3K/Akt pathway, a pathway involved in prostate cancer.[33]

Neurodevelopmental disorders

Single nucleotide polymorphisms (SNPs) in TCF7L2 gene have shown an increase in susceptibility to schizophrenia in Arab, European and Chinese Han populations.[citation needed] In the Chinese Han population, SNP rs12573128[10] in TCF7L2 is the variant that was associated with an increase in schizophrenia risk. This marker is used as a pre-diagnostic marker for schizophrenia.[10] TCF7L2 has also been reported as a risk gene in autism spectrum disorder[34] and has been linked to it in recent large-scale genetic studies.[11][12]

The mechanism behind TCF7L2's involvement in the emergence of neurodevelopmental disorders is not fully understood, as there have been few studies characterizing its role in brain development in detail. It was shown that during embryogenesis TCF7L2 is involved in the development of fish-specific habenula asymmetry in Danio rerio,[35][36] and that the dominant negative TCF7L2 isoform influences cephalic separation in the embryo by inhibiting the posteriorizing effect of the Wnt pathway.[37] It was also shown that in Tcf7l2 knockout mice the number of proliferating cells in cortical neural progenitor cells is reduced.[38] In contrast, no such effect was found in the midbrain.[39]

More recently it was shown that TCF7L2 plays a crucial role in both the embryonic development and postnatal maturation of the thalamus through direct and indirect regulation of many genes previously reported to be important for both processes.[19] In late gestation TCF7L2 regulates the expression of many thalamus-enriched transcription factors (e.g. Foxp2, Rora, Mef2a, Lef1, Prox1), axon guidance molecules (e.g. Epha1, Epha4, Ntng1, Epha8) and cell adhesion molecules (e.g. Cdh6, Cdh8, Cdhr1). Accordingly, a total knockout of Tcf7l2 in mice leads to improper growth of thalamocortical axons, changed anatomy and improper sorting of the cells in the thalamo-habenular region.[19] In the early postnaral period TCF7L2 starts to regulate the expression of many genes necessary for the acquisition of characteristic excitability patterns in the thalamus, mainly ion channels, neurotransmitters and their receptors and synaptic vescicle proteins (e.g. Cacna1g, Kcnc2, Slc17a7, Grin2b), and an early postnatal knockout of Tcf7l2 in mouse thalamus leads to significant reduction in the number and frequency of action potentials generated by the thalamocortical neurons.[19] The mechanism that leads to the change in TCF7L2 target genes between gestation and early postnatal period is unknown. It is likely that a perinatal change in the proportion of TCF7L2 isoforms expressed in the thalamus is partially responsible.[24] Abnormalities in the anatomy of the thalamus and the activity of its connections to the cerebral cortex are frequently detected in patients with schizophrenia [40][41][42][43] and autism.[44][45][46][47] Such abnormalities could arise from developmental aberrations in patients with unfavorable mutations of TCF7L2, further strengthening the link between TCF7L2 and neurodevelopmental disorders.

Multiple sclerosis

TCF7L2 is downstream of the WNT/β-catenin pathways. The activation of the WNT/β-catenin pathways have been associated demyelination in multiple sclerosis.[14] TCF7L2 is unregulated during early remyelination, leading scientists to believe that it is involved in remyelination.[14] TCF7L2 could act in dependence or independent of the WNT/β-catenin pathways.[14]

Model organisms

Model organisms have been used in the study of TCF7L2 function. A conditional knockout mouse line called Tcf7l2tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[48] Male and female animals underwent a standardized phenotypic screen[49] to determine the effects of deletion.[50][51][52][53] Additional screens performed: - In-depth immunological phenotyping[54]

Variations of the protein encoding gene are found in rats, zebra fish, drosophila, and budding yeast.[55] Therefore, all of those organisms can be used as model organisms in the study of TCF7L2 function.

Nomenclature

TCF7L2 is the symbol officially approved by the HUGO Gene Nomenclature Committee for the Transcription Factor 7-Like 2 gene.

See also

  • TCF/LEF family

References

  1. ↑ "Entrez Gene: TCF7L2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6934. 
  2. ↑ "A gene family of HMG-box transcription factors with homology to TCF-1". Nucleic Acids Research 20 (3): 611. February 1992. doi:10.1093/nar/20.3.611. PMID 1741298. 
  3. ↑ 3.0 3.1 "TCF7L2 transcription factor 7 like 2 [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/6934. 
  4. ↑ 4.0 4.1 4.2 4.3 Online Mendelian Inheritance in Man (OMIM) TRANSCRIPTION FACTOR 7-LIKE 2;TCF7L2 -602228{
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus". Molecular Endocrinology 22 (11): 2383–2392. November 2008. doi:10.1210/me.2008-0135. PMID 18599616. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Genetic variants and the risk of gestational diabetes mellitus: a systematic review". Human Reproduction Update 19 (4): 376–390. 2013-05-19. doi:10.1093/humupd/dmt013. PMID 23690305. 
  7. ↑ Deciphering Developmental Disorders Study et al. (March 2015). "Large-scale discovery of novel genetic causes of developmental disorders". Nature 519 (7542): 223–228. doi:10.1038/nature14135. PMID 25533962. Bibcode: 2015Natur.519..223T. 
  8. ↑ Deciphering Developmental Disorders Study et al. (February 2017). "Prevalence and architecture of de novo mutations in developmental disorders". Nature 542 (7642): 433–438. doi:10.1038/nature21062. PMID 28135719. Bibcode: 2017Natur.542..433M. 
  9. ↑ "At-risk variant in TCF7L2 for type II diabetes increases risk of schizophrenia" (in English). Biological Psychiatry 70 (1): 59–63. July 2011. doi:10.1016/j.biopsych.2011.01.031. PMID 21414605. 
  10. ↑ 10.0 10.1 10.2 "TCF7L2 polymorphisms and the risk of schizophrenia in the Chinese Han population". Oncotarget 8 (17): 28614–28620. April 2017. doi:10.18632/oncotarget.15603. PMID 28404897. 
  11. ↑ 11.0 11.1 "Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders". Nature Communications 11 (1): 4932. October 2020. doi:10.1038/s41467-020-18723-y. PMID 33004838. Bibcode: 2020NatCo..11.4932W. 
  12. ↑ 12.0 12.1 "Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism". Cell 180 (3): 568–584.e23. February 2020. doi:10.1016/j.cell.2019.12.036. PMID 31981491. 
  13. ↑ 13.0 13.1 13.2 "Proteomic Characterization of Transcription and Splicing Factors Associated with a Metastatic Phenotype in Colorectal Cancer". Journal of Proteome Research 17 (1): 252–264. January 2018. doi:10.1021/acs.jproteome.7b00548. PMID 29131639. 
  14. ↑ 14.0 14.1 14.2 14.3 "Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis". Cellular and Molecular Neurobiology 38 (4): 783–795. May 2018. doi:10.1007/s10571-017-0550-9. PMID 28905149. 
  15. ↑ "Using gene-network landscape to dissect genotype effects of TCF7L2 genetic variant on diabetes and cardiovascular risk". Physiological Genomics 44 (19): 903–914. October 2012. doi:10.1152/physiolgenomics.00030.2012. PMID 22872755. 
  16. ↑ PDB: 2GL7​; "Crystal structure of a beta-catenin/BCL9/Tcf4 complex". Molecular Cell 24 (2): 293–300. October 2006. doi:10.1016/j.molcel.2006.09.001. PMID 17052462. 
  17. ↑ "The epithelial-mesenchymal transition: new insights in signaling, development, and disease". The Journal of Cell Biology 172 (7): 973–981. March 2006. doi:10.1083/jcb.200601018. PMID 16567498. 
  18. ↑ "Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration". Scientific Reports 7 (1): 9605. August 2017. doi:10.1038/s41598-017-09867-x. PMID 28851992. Bibcode: 2017NatSR...7.9605F. 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 "TCF7L2 regulates postmitotic differentiation programmes and excitability patterns in the thalamus". Development 147 (16): dev.190181. August 2020. doi:10.1242/dev.190181. PMID 32675279. 
  20. ↑ 20.0 20.1 "Detection of SNPs of T2DM susceptibility genes by a ligase detection reaction-fluorescent nanosphere technique". Analytical Biochemistry 540-541 (Supplement C): 38–44. January 2018. doi:10.1016/j.ab.2017.11.003. PMID 29128291. 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 "TCF7L2 rs290481 T>C polymorphism is associated with an increased risk of type 2 diabetes mellitus and fasting plasma glucose level". Oncotarget 8 (44): 77000–77008. September 2017. doi:10.18632/oncotarget.20300. PMID 29100364. 
  22. ↑ Database, GeneCards Human Gene. "TCF7L2 Gene - GeneCards | TF7L2 Protein | TF7L2 Antibody". https://www.genecards.org/cgi-bin/carddisp.pl?gene=TCF7L2. 
  23. ↑ "TCF7L2 - Transcription factor 7-like 2 - Homo sapiens (Human) - TCF7L2 gene & protein" (in en). https://www.uniprot.org/uniprot/Q9NQB0. 
  24. ↑ 24.0 24.1 "Postnatal isoform switch and protein localization of LEF1 and TCF7L2 transcription factors in cortical, thalamic, and mesencephalic regions of the adult mouse brain". Brain Structure & Function 218 (6): 1531–1549. November 2013. doi:10.1007/s00429-012-0474-6. PMID 23152144. 
  25. ↑ "Molecular correlates of laminar differences in the macaque dorsal lateral geniculate nucleus". The Journal of Neuroscience 28 (46): 12010–12022. November 2008. doi:10.1523/JNEUROSCI.3800-08.2008. PMID 19005066. 
  26. ↑ 26.0 26.1 "TCF7L2 and glucose metabolism: time to look beyond the pancreas". Diabetes 62 (3): 706–708. March 2013. doi:10.2337/db12-1418. PMID 23431017. 
  27. ↑ "Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans". American Journal of Human Genetics 64 (4): 1127–1140. April 1999. doi:10.1086/302316. PMID 10090898. 
  28. ↑ "Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes". Nature Genetics 38 (3): 320–323. March 2006. doi:10.1038/ng1732. PMID 16415884. 
  29. ↑ "Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis". Endocrine Reviews 37 (3): 254–277. June 2016. doi:10.1210/er.2015-1146. PMID 27159876. 
  30. ↑ "Transcription factor 7-like 2 polymorphism and colon cancer". Cancer Epidemiology, Biomarkers & Prevention 17 (4): 978–982. April 2008. doi:10.1158/1055-9965.EPI-07-2687. PMID 18398040. 
  31. ↑ "Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk". Cancer Causes & Control 19 (9): 975–980. November 2008. doi:10.1007/s10552-008-9164-3. PMID 18478343. 
  32. ↑ "A genome-wide RNAi screen for Wnt/beta-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer". Proceedings of the National Academy of Sciences of the United States of America 105 (28): 9697–9702. July 2008. doi:10.1073/pnas.0804709105. PMID 18621708. Bibcode: 2008PNAS..105.9697T. 
  33. ↑ "Positive inter-regulation between beta-catenin/T cell factor-4 signaling and endothelin-1 signaling potentiates proliferation and survival of prostate cancer cells". Molecular Pharmacology 69 (2): 520–531. February 2006. doi:10.1124/mol.105.019620. PMID 16291872. 
  34. ↑ "SFARI Gene Databse - TCF7L2" (in en-US). https://gene.sfari.org/database/human-gene/TCF7L2. 
  35. ↑ "The ventral habenulae of zebrafish develop in prosomere 2 dependent on Tcf7l2 function". Neural Development 8 (1): 19. September 2013. doi:10.1186/1749-8104-8-19. PMID 24067090. 
  36. ↑ "Tcf7l2 is required for left-right asymmetric differentiation of habenular neurons". Current Biology 24 (19): 2217–2227. October 2014. doi:10.1016/j.cub.2014.08.006. PMID 25201686. 
  37. ↑ "A novel mechanism for the transcriptional regulation of Wnt signaling in development". Genes & Development 25 (17): 1783–1795. September 2011. doi:10.1101/gad.17227011. PMID 21856776. 
  38. ↑ "Tcf7L2 is essential for neurogenesis in the developing mouse neocortex". Neural Development 13 (1): 8. May 2018. doi:10.1186/s13064-018-0107-8. PMID 29751817. 
  39. ↑ "Tcf7l2 plays crucial roles in forebrain development through regulation of thalamic and habenular neuron identity and connectivity". Developmental Biology 424 (1): 62–76. April 2017. doi:10.1016/j.ydbio.2017.02.010. PMID 28219675. 
  40. ↑ "Running in the Family? Structural Brain Abnormalities and IQ in Offspring, Siblings, Parents, and Co-twins of Patients with Schizophrenia". Schizophrenia Bulletin 45 (6): 1209–1217. October 2019. doi:10.1093/schbul/sby182. PMID 30597053. 
  41. ↑ "Review of thalamocortical resting-state fMRI studies in schizophrenia". Schizophrenia Research. Pathologies of the Thalamus in Schizophrenia 180: 58–63. February 2017. doi:10.1016/j.schres.2016.08.005. PMID 27531067. 
  42. ↑ "Altered functional connectivity between sub-regions in the thalamus and cortex in schizophrenia patients measured by resting state BOLD fMRI at 7T". Schizophrenia Research 206: 370–377. April 2019. doi:10.1016/j.schres.2018.10.016. PMID 30409697. 
  43. ↑ "Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium". Biological Psychiatry 84 (9): 644–654. November 2018. doi:10.1016/j.biopsych.2018.04.023. PMID 29960671. 
  44. ↑ "Thalamocortical connectivity is associated with autism symptoms in high-functioning adults with autism and typically developing adults". Translational Psychiatry 11 (1): 93. February 2021. doi:10.1038/s41398-021-01221-0. PMID 33536431. 
  45. ↑ "Morphological Alterations in the Thalamus, Striatum, and Pallidum in Autism Spectrum Disorder". Neuropsychopharmacology 41 (11): 2627–2637. October 2016. doi:10.1038/npp.2016.64. PMID 27125303. 
  46. ↑ "Reduced Local and Increased Long-Range Functional Connectivity of the Thalamus in Autism Spectrum Disorder". Cerebral Cortex 29 (2): 573–585. February 2019. doi:10.1093/cercor/bhx340. PMID 29300843. 
  47. ↑ "Thalamocortical dysconnectivity in autism spectrum disorder: An analysis of the Autism Brain Imaging Data Exchange". Biological Psychiatry. Cognitive Neuroscience and Neuroimaging 2 (1): 76–84. January 2017. doi:10.1016/j.bpsc.2016.09.002. PMID 28584881. 
  48. ↑ "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. 2010. doi:10.1111/j.1755-3768.2010.4142.x. 
  49. ↑ "International Mouse Phenotyping Consortium". http://www.mousephenotype.org/data/search?q=Tcf7l2#fq=*:*&facet=gene. 
  50. ↑ "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–342. June 2011. doi:10.1038/nature10163. PMID 21677750. 
  51. ↑ "Mouse library set to be knockout". Nature 474 (7351): 262–263. June 2011. doi:10.1038/474262a. PMID 21677718. 
  52. ↑ "A mouse for all reasons". Cell 128 (1): 9–13. January 2007. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  53. ↑ "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–464. July 2013. doi:10.1016/j.cell.2013.06.022. PMID 23870131. 
  54. ↑ "Infection and Immunity Immunophenotyping (3i) Consortium". http://www.immunophenotyping.org/data/search?keys=Tcf7l2&field_gene_construct_tid=All. 
  55. ↑ "MARRVEL: Search Result". http://marrvel.org/search/gene/TCF7L2. 

Further reading

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) - [1]
  • Weizmann Institute GeneCard for TCF7L2
  • Overview of all the structural information available in the PDB for UniProt: Q9NQB0 (Transcription factor 7-like 2) at the PDBe-KB.



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