Alternative titles; symbols
HGNC Approved Gene Symbol: TCF7L1
Cytogenetic location: 2p11.2 Genomic coordinates (GRCh38): 2:85,133,392-85,310,387 (from NCBI)
TCF/LEF transcription factors, such as TCF7L1, are mediators of the Wnt (see 164820) signaling pathway and are antagonized by the TGF-beta (TGFB1; 190180) signaling pathway (Sagara and Katoh, 2000).
The high mobility group (HMG) box is a DNA-binding domain. TCF7 (189908), also called TCF1, and LEF1 (153245), also called TCF1-alpha, are human lymphoid transcription factors that contain a virtually identical HMG box. By PCR of human genomic DNA using degenerate oligonucleotides based on the HMG boxes of TCF7 and LEF1, Castrop et al. (1992) identified the TCF7L1 and TCF7L2 (602228) genes, which they called TCF3 and TCF4, respectively. TCF7L1 and TCF7L2 were not expressed in cells of lymphoid lineage. The deduced amino acid sequences of the HMG boxes of TCF7L1, TCF7L2, and TCF7 show striking homology. The authors suggested the existence of a subfamily of TCF7-like HMG box-containing transcription factors.
By searching databases for homologs of mouse Tcf3, followed by PCR of a small intestine cDNA library and screening of a fetal lung cDNA library, Sagara and Katoh (2000) cloned human TCF7L1, which they called TCF3. The deduced 588-amino acid protein contains a beta-catenin (CTNNB1; 116806)-binding domain at its N terminus, followed by an HMG box, a nuclear translocation signal, and 2 putative CTBP (see 602618)-binding sites at its C terminus. TCF7L1 shares 58% amino acid identity with TCF7L2, its closest homolog among human TCF proteins. Northern blot analysis detected a 3.0-kb TCF7L1 transcript in human stomach and in some human gastric cancer cell lines.
Using Northern blot analysis, Sagara and Katoh (2000) found that TCF7L1 was occasionally upregulated in primary gastric cancer compared with normal gastric mucosa. Overexpression of TCF7L1 in MKN28 human gastric cancer cell lines resulted in 8-fold resistance to mitomycin C compared with controls. DTD (NQO1; 125860) mRNA was downregulated in MKN28 cell lines overexpressing TCF7L1 and in primary gastric cancer with TCF7L1 upregulation. The DTD protein, which is implicated in mitomycin C activation, was also downregulated in MKN28 cell lines overexpressing TCF7L1. Sagara and Katoh (2000) concluded that mitomycin C resistance induced by TCF7L1 overexpression in gastric cancer is likely due to DTD downregulation.
Merrill et al. (2001) showed that Lef1 and Tcf3 controlled differentiation of multipotent stem cells in mouse skin. Lef1 required Wnt signaling and stabilized beta-catenin to express hair-specific keratins and control hair differentiation. In contrast, Tcf3 acted independently of its beta-catenin-interacting domain to suppress features of epidermal differentiation, in which Tcf3 was normally shut off, and promote features of the follicle outer root sheath and multipotent stem cells.
By immunofluorescence analysis, Nguyen et al. (2006) found that embryonic mouse skin progenitors expressed Tcf3. Using an inducible Tcf3 expression system in mice, they showed that postnatal Tcf3 reactivation caused committed epidermal cells to induce genes associated with an undifferentiated, Wnt-inhibited state, and that Tcf3 promoted a transcriptional program shared by embryonic and postnatal stem cells. Genes repressed by Tcf3 included transcriptional regulators of the epidermal, sebaceous gland, and hair follicle differentiation programs, and all 3 terminal differentiation pathways were suppressed by postnatal Tcf3 induction. Nguyen et al. (2006) concluded that, in the absence of Wnt signals, Tcf3 functions in skin stem cells to maintain an undifferentiated state, and that through Wnt signaling, Tcf3 directs these cells along the hair lineage.
To balance self-renewal and differentiation, embryonic stem (ES) cells must control the levels of several transcription factors, including NANOG (607937). Pereira et al. (2006) showed that Tcf3 limited the steady-state levels of Nanog mRNA, protein, and promoter activity in self-renewing mouse ES cells. Chromatin immunoprecipitation and promoter reporter assays showed that Tcf3 bound to a promoter regulatory region of the Nanog gene and repressed its transcriptional activity. Repression of Nanog required the groucho (see 600189) interaction domain of Tcf3. Absence of Tcf3 delayed differentiation of ES cells in vitro by allowing elevated Nanog levels to persist through 5 days of embryoid body formation. Pereira et al. (2006) concluded that TCF3-mediated control of NANOG expression allows ES cells to balance the creation of lineage-committed and undifferentiated cells.
Nguyen et al. (2009) found that knockout of Tcf3 or Tcf4 individually had no overt effect on hair phenotype in mice, but Tcf3/Tcf4 double knockout resulted in a severe skin and hair defects. Newborn Tcf3/Tcf4-null skin was thinner than normal and often lacked whiskers. Tcf3/Tcf4-null skin showed signs of apoptosis and, when grafted onto nude mice, became shrunken, was unable to repair wounds, and was progressively lost, showing an inability to maintain long-term self-renewing populations of skin epithelia. Tcf3/Tcf4-null skin cells grew poorly in culture and did not survive passaging. Microarray analysis of mRNAs expressed by normal and Tcf3/Tcf4-null skin suggested that Tcf3 and Tcf4 maintain skin epithelial stem cells through Wnt-dependent and Wnt-independent signaling.
The TCF7L1 gene, although initially designated TCF3, should not be confused with the TCF3 gene (147141), also known as E2A. TCF7L1 encodes a TCF/LEF transcription factor involved in Wnt signaling, whereas TCF3 encodes the basic helix-loop-helix (bHLH) transcription factors E12 and E47.
Castrop, J., van Norren, K., Clevers, H. A gene family of HMG-box transcription factors with homology to TCF-1. Nucleic Acids Res. 20: 611 only, 1992. [PubMed: 1741298] [Full Text: https://doi.org/10.1093/nar/20.3.611]
Merrill, B. J., Gat, U., DasGupta, R., Fuchs, E. Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev. 15: 1688-1705, 2001. [PubMed: 11445543] [Full Text: https://doi.org/10.1101/gad.891401]
Nguyen, H., Merrill, B. J., Polak, L., Nikolova, M., Rendl, M., Shaver, T. M., Pasolli, H. A., Fuchs, E. Tcf3 and Tcf4 are essential for long-term homeostasis of skin epithelia. Nature Genet. 41: 1068-1075, 2009. [PubMed: 19718027] [Full Text: https://doi.org/10.1038/ng.431]
Nguyen, H., Rendl, M., Fuchs, E. Tcf3 governs stem cell features and represses cell fate determination in skin. Cell 127: 171-183, 2006. [PubMed: 17018284] [Full Text: https://doi.org/10.1016/j.cell.2006.07.036]
Pereira, L., Yi, F., Merrill, B. J. Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal. Molec. Cell. Biol. 26: 7479-7491, 2006. [PubMed: 16894029] [Full Text: https://doi.org/10.1128/MCB.00368-06]
Sagara, N., Katoh, M. Mitomycin C resistance induced by TCF-3 overexpression in gastric cancer cell line MKN28 is associated with DT-diaphorase down-regulation. Cancer Res. 60: 5959-5962, 2000. [PubMed: 11085512]