Transcription factor 7-like 2 , also known as TCF7L2 or TCF4, is a protein acting as a transcription factor that, in humans, is encoded by the TCF7L2gene. The TCF7L2 gene is located on chromosome 10q25.2–q25.3, contains 19 exons and has autosomal dominant inheritance. The TCF7L2 gene is polymorphic and pleiotropic. As a member of the TCF family, TCF7L2 can form a bipartite transcription factor and influence several biological pathways, including the Wnt signalling pathway. Single-nucleotide polymorphisms in this gene are especially known to be linked to higher risk to develop type 2 diabetes, gestational diabetes and multiple other diseases. The SNP rs7903146, within the TCF7L2 gene, is, to date, the most significant genetic marker associated with type 2 diabetes risk.
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 alongside β-catenin. Bipartite transcription factors can have large effects on the Wnt signalling pathway. Stimulation of the Wnt signaling pathway leads to the association of β-catenin with BCL9, translocation to the nucleus, and association with TCF7L2, 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. The repression of TCF7L2 using HMG-box repressor inhibits Wnt signalling. 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. 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 and rs290481T>C polymorphisms. TCF7L2 rs290481T>C polymorphism, however, has shown no significant correlation to the susceptibility to gestational diabetes mellitus in a Chinese Han population, whereas the T alleles of rs7903146 and rs1799884 increase susceptibility to GDM in the Chinese Han population. 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 and has autosomal dominant inheritance. Of the 19 exons, 5 are alternative. The TCF7L2 protein contains 619 amino acids and its molecular mass is 67919 Da. TCF7L2's secondary structure is a helix-turn-helix structure.
Tissue distribution
TCF7L2 is primarily expressed in brain, liver, intestine and fat cells. It does not primarily operate in the β-cells in the pancreas.
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 This signal was later refined by Struan Grant and colleagues at DeCODE genetics and isolated to the TCF7L2 gene. 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. TCF7L2 polymorphisms can increase susceptibility to type 2 diabetes by decreasing the production of glucagon-like peptide-1.
Gestational Diabetes (GDM)
TCF7L2 modulates pancreatic islet β-cell function strongly implicating its significant association with GDM risk. T alleles of rs7903146 and rs1799884 TCF7L2 polymorphisms increase susceptibility to GDM in the Chinese Han population.
Cancer
TCF7L2 plays a role in colorectal cancer. A frameshift mutation of TCF7L2 provided evidence that TCF7L2 is implicated in colorectal cancer. 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. Variants of the gene are most likely involved in many other cancer types. TCF7L2 is indirectly involved in prostate cancer through its role in activating the PI3K/Akt pathway, a pathway involved in prostate cancer.
Schizophrenia
Single nucleotide polymorphisms in TCF7L2 gene have shown an increase in susceptibility to schizophrenia in Arab, European and Chinese Han populations. In the Chinese Han population, SNP rs12573128 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.
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. TCF7L2 is unregulated during early remyelination, leading scientists to believe that it is involved in remyelination. TCF7L2 could act in dependence or independent of the WNT/β-catenin pathways.
Model organisms
s have been used in the study of TCF7L2 function. A conditional knockout mouse line called Tcf7l2tm1aWtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping Variations of the protein encoding gene are found in rats, zebra fish, drosophila, and budding yeast. Therefore, all of those organisms can be used as model organisms in the study of TCF7L2 function.
