Alternative titles; symbols
HGNC Approved Gene Symbol: ZEB1
Cytogenetic location: 10p11.22 Genomic coordinates (GRCh38): 10:31,318,417-31,529,804 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p11.22 | Corneal dystrophy, Fuchs endothelial, 6 | 613270 | Autosomal dominant | 3 |
| Corneal dystrophy, posterior polymorphous, 3 | 609141 | Autosomal dominant | 3 |
ZEB1 encodes a zinc finger transcription factor that represses T-lymphocyte-specific IL2 gene (147680) expression by binding to a negative regulatory domain 100 nucleotides 5-prime of the IL2 transcription start site (Williams et al., 1991).
By Northern blot analysis in adult rat tissue, Nishimura et al. (2006) found that delta-Ef1 was expressed in aorta, heart, carotid artery, brain, and skeletal muscle, but not in visceral smooth muscle tissues, such as bladder, stomach, and small intestine. In mice, delta-Ef1 was expressed in the media of arteries and in cardiomyocytes. Positively stained cells were also occasionally observed in veins, but not in arterial endothelial cells.
Williams et al. (1992) used Southern hybridization and somatic cell hybrids to demonstrate that the murine and human genomes contain homologous genes and that the ZEB1 gene resides on human chromosome 10. Fluorescence in situ hybridization localized the ZEB1 gene to chromosome 10p11.2.
Krafchak et al. (2005) demonstrated a complex (core plus secondary) binding site for TCF8 in the promoter of the COL4A3 gene (120070), mutant in Alport syndrome (e.g., 104200) and which encodes collagen type IV alpha-3. They detected expression of TCF8 in cornea.
Nishimura et al. (2006) found that delta-Ef1 was upregulated during differentiation in a mouse smooth muscle cell (SMC) line. Delta-Ef1 selectively transactivated the promoters of the SMC differentiation marker genes Acta2 (102620) and Myh11 (160745), and it physically interacted with Srf (600589) and Smad3 (603109), resulting in synergistic activation of the Acta2 promoter. Chromatin immunoprecipitation assays and knockdown experiments showed that delta-Ef1 was involved in control of SMC differentiation programs induced by Tgf-beta (TGFB1; 190180) signaling. Overexpression of delta-Ef1 inhibited neointima formation and promoted SMC differentiation.
TGF-beta is a key regulator of extracellular matrix collagens in mesangial cells (MCs) in diabetic nephropathy. Kato et al. (2007) found that TGF-beta increased miR192 (MIRN192; 610939) levels in primary mouse MCs, and they identified Sip1 (ZEB2; 605802) as a target of miR192 in mouse MCs. TGF-beta treatment or transfection with miR192 decreased expression of endogenous Sip1 and activity of a reporter construct containing the 3-prime UTR of Sip1. Conversely, inhibition of miR192 enhanced reporter activity, confirming Sip1 to be an miR192 target. Glomeruli isolated from streptozotocin-injected diabetic mice and diabetic db/db mice (see 601007) showed elevated miR192 levels relative to corresponding nondiabetic controls, which paralleled increased Tgf-beta and Col1a2 (120160) expression. Transfection of mouse MCs with miR192 and short hairpin RNAs targeting delta-EF1 synergistically enhanced activity of a reporter construct containing upstream E-box elements of the Col1a2 gene. Kato et al. (2007) concluded that TGF-beta-mediated collagen regulation in MCs involves crosstalk between miR192 and the E-box repressors delta-EF1 and SIP1.
Park et al. (2008) found that expression of the miR200 family of microRNAs (e.g., MIRN200A; 612090) in human cell lines was associated with an epithelial phenotype and with expression of E-cadherin (CDH1; 192090), an epithelial cell marker. They identified multiple miR200 target sequences in the 3-prime UTRs of the E-cadherin transcriptional repressors ZEB1 and ZEB2. Using the 3-prime UTRs of mouse and human ZEB1 and ZEB2, they showed that endogenous miR200s suppressed ZEB1 and ZEB2 expression. Increasing miR200 levels induced mesenchymal-to-epithelial transition (MET) in human cancer cell lines, reducing their aggressiveness. Conversely, reducing miR200 levels induced epithelial-to-mesenchymal transition (EMT). Park et al. (2008) concluded that the miR200 family regulates EMT/MET by targeting ZEB1 and ZEB2, which control expression of E-cadherin.
Uterine quiescence during pregnancy is mediated by increased progesterone, which represses factors involved in contraction. Renthal et al. (2010) identified MIRN200 family members (MIRN200B, 612091; MIRN429, 612094) as microRNAs that mediate myometrial transition to a contractile phenotype. In human and mouse uterus during pregnancy, Renthal et al. (2010) found that ZEB1 and ZEB2 were transcriptional repressors of the contraction-associated genes connexin-43 (GJA1; 121014) and the oxytocin receptor (OXTR; 167055) in myometrial cells. ZEB1 was directly upregulated by progesterone at the ZEB1 promoter. During preterm labor in mice, there was an upregulation of Mirn200b/Mirn429, which downregulated Zeb1 and Zeb2, resulting in derepression of transcription of the contractility-associated proteins. In addition, Zeb1 was found to directly bind and repress Mirn200b/Mirn429, indicating a feedback mechanism. The findings implicated MIRN200B/MIRN429 and their targets, ZEB1 and ZEB2, as unique progesterone-mediated regulators of uterine quiescence and contractility during pregnancy and labor.
Hasuwa et al. (2013) described anovulation and infertility in female mice lacking the microRNAs miR200b and miR429. Both miRNAs are strongly expressed in the pituitary gland, where they suppress expression of the transcriptional repressor Zeb1. Eliminating these miRNAs, in turn, inhibits luteinizing hormone (LH) synthesis by repressing transcription of its beta-subunit gene (LHB; 152780), which leads to lowered serum LH concentration, an impaired LH surge, and failure to ovulate. Hasuwa et al. (2013) concluded that these results revealed roles for miR200b and miR429, and their target the ZEB1 gene, in the regulation of mammalian reproduction. Thus, the hypothalamo-pituitary-ovarian axis requires miR200b and miR429 to support ovulation.
A high-mesenchymal cell state observed in human tumors and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages. Viswanathan et al. (2017) molecularly characterized this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and showed that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a nonapoptotic form of cell death induced by the build-up of toxic lipid peroxides. Viswanathan et al. (2017) showed that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4; 138322), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGF-beta (190180)-mediated therapy resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. Viswanathan et al. (2017) identified vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.
Using biochemical and genetic screens, Manshouri et al. (2019) showed that the nucleosome remodeling and deacetylase (NURD) complex interacted with ZEB1 in nonsmall cell lung cancer (NSCLC; see 211980) cells and functioned as a ZEB1 corepressor. The authors identified TBC1D2B (619152) as a target of the ZEB1/NURD complex. TBC1D2B downregulation by the ZEB1/NURD complex increased RAB22 (RAB22A; 612966) activation and promoted E-cadherin internalization and degradation, enhancing metastasis of NSCLC.
Posterior Polymorphous Corneal Dystrophy 3
In the original family with posterior polymorphous corneal dystrophy-3 (PPCD3; 609141) described by Moroi et al. (2003), Krafchak et al. (2005) detected a heterozygous frameshift mutation in TCF8 (189909.0001) that segregated with PPCD and 4 different heterozygous nonsense and frameshift mutations in TCF8 in 4 other PPCD probands (see, e.g., 189909.0002). Identification of TCF8 as the PPCD3 gene provided a valuable tool for the study of critical gene regulation events in PPCD pathology and suggested a possible role for TCF8 mutations in altered structure and function of cells lining body cavities other than the anterior chamber of the eye. This study identified TCF8 as the gene responsible for approximately half of the cases of PPCD, implicated TCF8 mutations in developmental abnormalities outside the eye, and revealed COL4A3, the TCF8 regulatory target, as a key, shared molecular component of 2 different diseases, PPCD and Alport syndrome.
In a cohort of 18 unrelated patients with PPCD, Lechner et al. (2013) performed Sanger sequencing of the ZEB1 gene and identified a previously reported frameshift mutation in an affected mother and son, as well as a nonsense mutation (S750X; 189909.0006) in a family from the United Kingdom with 6 affected individuals over 3 generations. Neither mutation was found in 96 controls or in public variant databases.
In a 64-year-old woman with keratoconus and PPCD, Fernandez-Gutierrez et al. (2023) analyzed 6 PPCD-associated genes and identified heterozygosity for a missense mutation in the ZEB1 gene (M1L; 189909.0007).
Fuchs Endothelial Corneal Dystrophy 6
Riazuddin et al. (2010) analyzed the ZEB1 gene in a total of 384 probands with late-onset Fuchs endothelial corneal dystrophy (FECD6; 613270) and identified 5 missense mutations in 7 patients (see, e.g., 189909.0003 and 189909.0004). One of the probands with the Q840P mutation (189909.0004) came from a large pedigree in which segregation analysis indicated that the 840P allele was sufficient but not necessary for pathogenesis. A genomewide scan in the pedigree identified an additional locus for late-onset FECD on chromosome 9p24.1-p22.1 (see FECD7, 613271); Riazuddin et al. (2010) suggested that mutations either in ZEB1 or at the 9p locus are sufficient for disease, and that genetic interaction between the 2 loci can lead to a more severe form of the disease.
In a cohort of 70 unrelated patients with keratoconus, Lechner et al. (2013) sequenced the ZEB1 gene and identified a heterozygous pathogenic missense substitution (Q640H; 189909.0005) in 1 proband; his mother, who had FECD, and his sister with keratoconus were also heterozygous for the variant, which was not found in 96 controls or public variant databases.
By direct sequencing of the ZEB1 gene in 82 patients from northern India with late-onset FECD, Gupta et al. (2015) identified a novel splice site mutation (IVS2+276C-T) in 11 patients (14%) as well as 2 novel missense mutations and 1 novel nonsense mutation in 1 patient each. One patient was found to have a previously identified missense mutation (189909.0004).
Nishimura et al. (2006) found that deletion of delta-Ef1 in mice was embryonic lethal. Aortic SMCs from delta-Ef1-null embryos exhibited retarded differentiation, although SMC differentiation marker genes, including Acta2 and Myh11, were still expressed. Vascular injury in delta-Ef1 +/- mice resulted in more prominent neointimal lesions than in wildtype mice. Reduced expression of Acta2 and Myh11 proteins in delta-Ef1 +/- mice indicated that redifferentiation of SMCs was disrupted.
The article by Li et al. (2016) regarding ZEB1-AS1 was retracted based on concerns of the journal regarding repetitive elements in several figures which were not addressed by the authors.
In the original family (UM:139) with posterior polymorphous corneal dystrophy-3 (PPCD3; 609141) described by Moroi et al. (2003), Krafchak et al. (2005) detected a heterozygous 2-bp deletion in the last exon of the TCF8 gene, c.2916_2917delTG (c.2916_2917delTG, NM_030751). This frameshift mutation was predicted to alter the amino acids downstream of the deletion and maintain an open reading frame for 13 codons before a termination signal, resulting in elimination of most of the last zinc finger cluster and the acidic activation domain. The mutation was present in all 13 affected family members who were screened.
In a family with posterior polymorphous corneal dystrophy-3 (PPCD3; 609141), Krafchak et al. (2005) detected a c.1350C-T transition (c.1350C-T, NM_030751) in exon 7 of the TCF8 gene. The mutation was predicted to result in elimination the homeodomain, the second cluster of zinc fingers, and the acidic activation domain.
In 2 unrelated patients with late-onset Fuchs endothelial corneal dystrophy-6 (FECD6; 613270), Riazuddin et al. (2010) identified heterozygosity for a 232A-G transition in the ZEB1 gene, resulting in an asn78-to-thr (N78T) substitution at an evolutionarily conserved residue. An in vivo complementation assay suggested that the N78T mutation is hypomorphic. The mutation was not found in 560 unrelated, ethnically matched controls or in HapMap samples of any ethnicity.
In 2 unrelated probands with late-onset Fuchs endothelial corneal dystrophy-6 (FECD6; 613270), Riazuddin et al. (2010) identified heterozygosity for a 2519A-C transversion in the ZEB1 gene, resulting in a gln840-to-pro (Q840P) substitution at an evolutionarily conserved residue. An in vivo complementation assay suggested that the Q840P mutation causes loss of function. The mutation was not found in 560 unrelated, ethnically matched controls or in HapMap samples of any ethnicity. One of the probands came from a large pedigree in which none of 7 unaffected members carried 840P, but the mutation was present in only 7 of 12 affected individuals. A genomewide scan in the pedigree identified an additional locus for late-onset FECD on chromosome 9p24.1-p22.1 (see FECD7, 613271). The 3 oldest of 5 individuals carrying both the Q840P mutation and the disease-transmitting haplotype on 9p had a severe FECD phenotype and all 3 had undergone corneal transplantation; Riazuddin et al. (2010) suggested that mutations either in ZEB1 or at the 9p locus are sufficient for disease, and that genetic interaction between the 2 loci can lead to a more severe form of the disease.
In 1 of 82 patients from northern India with late-onset FECD, Gupta et al. (2015) identified the Q840P mutation in the ZEB1 gene.
In a woman with Fuchs endothelial corneal dystrophy (FECD6; 613270), Lechner et al. (2013) identified heterozygosity for a c.1920G-T transversion (c.1920G-T, NM_030751.5) in exon 7 of the ZEB1 gene, resulting in a gln640-to-his (Q640H) substitution. Her son and daughter, who both had keratoconus but no evidence of FECD, were also heterozygous for the mutation, which was not found in 96 controls or in the 1000 Genomes Project or ESP databases. RT-qPCR analysis of cultured patient corneal keratocytes showed no change in expression of ZEB1 compared to control, but there was downregulation of alpha type IV basement membrane collagen genes (e.g., COL4A1, 120130).
In a family from the United Kingdom in which 6 members over 3 generations had posterior polymorphous corneal dystrophy (PPCD3; 609141), Lechner et al. (2013) identified heterozygosity for a c.2249C-A transversion (c.2249C-A, NM_030751.5) in exon 7, resulting in a ser750-to-ter (S750X) substitution and loss of the repression domain, the second zinc finger cluster, and the acidic activation domain. The mutation segregated fully with disease in the family, and was not found in 96 controls or in the dbSNP, 1000 Genomes Project, or ESP databases.
In a 64-year-old woman with posterior polymorphous corneal dystrophy (PPCD3; 609141), Fernandez-Gutierrez et al. (2023) identified heterozygosity for a c.1A-C transversion (c.1A-C, NM_030751) resulting in a met1-to-leu (M1L) substitution. Her unaffected 36-year-old son, who had normal biomicroscopy and specular microscopy findings, did not carry the mutation.
Fernandez-Gutierrez, E., Fernandez-Perez, P., Boto-De-Los-Bueis, A., Garcia-Fernandez, L., Rodriguez-Solana, P., Solis, M., Vallespin, E. Posterior polymorphous corneal dystrophy in a patient with a novel ZEB1 gene mutation. Int. J. Molec. Sci. 24: 209, 2023. [PubMed: 36613650] [Full Text: https://doi.org/10.3390/ijms24010209]
Gupta, R., Kumawat, B. L., Paliwal, P., Tandon, R., Sharma, N., Sen, S., Kashyap, S., Nag, T. C., Vajpayee, R. B., Sharma, A. Association of ZEB1 and TCF4 rs613872 changes with late onset Fuchs endothelial corneal dystrophy in patients from northern India. Molec. Vision 21: 1252-1260, 2015. [PubMed: 26622166]
Hasuwa, H., Ueda, J., Ikawa, M., Okabe, M. MiR-200b and miR-429 function in mouse ovulation and are essential for female fertility. Science 341: 71-73, 2013. [PubMed: 23765281] [Full Text: https://doi.org/10.1126/science.1237999]
Kato, M., Zhang, J., Wang, M., Lanting, L., Yuan, H., Rossi, J. J., Natarajan, R. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc. Nat. Acad. Sci. 104: 3432-3437, 2007. [PubMed: 17360662] [Full Text: https://doi.org/10.1073/pnas.0611192104]
Krafchak, C. M., Pawar, H., Moroi, S. E., Sugar, A., Lichter, P. R., Mackey, D. A., Mian, S., Nairus, T., Elner, V., Schteingart, M. T., Downs, C. A., Kijek, T. G., and 9 others. Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. Am. J. Hum. Genet. 77: 694-708, 2005. [PubMed: 16252232] [Full Text: https://doi.org/10.1086/497348]
Lechner, J., Dash, D. P., Muszynska, D., Hosseini, M., Segev, F., George, S., Frazer, D. G., Moore, J. E., Kaye, S. B., Young, T., Simpson, D. A., Churchill, A. J., Heon, E., Willoughby, C. E. Mutational spectrum of the ZEB1 gene in corneal dystrophies supports a genotype-phenotype correlation. Invest. Ophthal. Vis. Sci. 54: 3215-3223, 2013. [PubMed: 23599324] [Full Text: https://doi.org/10.1167/iovs.13-11781]
Li, T., Xie, J., Shen, C., Cheng, D., Shi, Y., Wu, Z., Deng, X., Chen, H., Shen, B., Peng, C., Li, H., Zhan, Q., Zhu, Z. Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma. Oncogene 35: 1575-1584, 2016. Note: Retraction: Oncogene 41: 4839 only, 2022. [PubMed: 26073087] [Full Text: https://doi.org/10.1038/onc.2015.223]
Manshouri, R., Coyaud, E., Kundu, S. T., Peng, D. H., Stratton, S. A., Alton, K., Bajaj, R., Fradette, J. J., Minelli, R., Peoples, M. D., Carugo, A., Chen, F., Bristow, C., Kovacs, J. J., Barton, M. C., Heffernan, T., Creighton, C. J., Raught, B., Gibbons, D. L. ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer. Nature Commun. 10: 5125, 2019. Note: Electronic Article. [PubMed: 31719531] [Full Text: https://doi.org/10.1038/s41467-019-12832-z]
Moroi, S. E., Gokhale, P. A., Schteingart, M. T., Sugar, A., Downs, C. A., Shimizu, S., Krafchak, C., Fuse, N., Elner, S. G., Elner, V. M., Flint, A., Epstein, M. P., Boehnke, M., Richards, J. E. Clinicopathologic correlation and genetic analysis in a case of posterior polymorphous corneal dystrophy. Am. J. Ophthal. 135: 461-470, 2003. [PubMed: 12654361] [Full Text: https://doi.org/10.1016/s0002-9394(02)02032-9]
Nishimura, G., Manabe, I., Tsushima, K., Fujiu, K., Oishi, Y., Imai, Y., Maemura, K., Miyagishi, M., Higashi, Y., Kondoh, H., Nagai, R. Delta-EF1 mediates TGF-beta signaling in vascular smooth muscle cell differentiation. Dev. Cell 11: 93-104, 2006. [PubMed: 16824956] [Full Text: https://doi.org/10.1016/j.devcel.2006.05.011]
Park, S.-M., Gaur, A. B., Lengyel, E., Peter, M. E. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22: 894-907, 2008. Note: Erratum: Genes Dev. 23: 1378 only, 2009. [PubMed: 18381893] [Full Text: https://doi.org/10.1101/gad.1640608]
Renthal, N. E., Chen, C.-C., Williams. K. C., Gerard, R. D., Prange-Kiel, J., Mendelson, C. R. miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor. Proc. Nat. Acad. Sci. 107: 20828-20833, 2010. [PubMed: 21079000] [Full Text: https://doi.org/10.1073/pnas.1008301107]
Riazuddin, S. A., Zaghloul, N. A., Al-Saif, A., Davey, L., Diplas, B. H., Meadows, D. N., Eghrari, A. O., Minear, M. A., Li, Y.-J., Klintworth, G. K., Afshari, N., Gregory, S. G., Gottsch, J. D., Katsanis, N. Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am. J. Hum. Genet. 86: 45-53, 2010. [PubMed: 20036349] [Full Text: https://doi.org/10.1016/j.ajhg.2009.12.001]
Viswanathan, V. S., Ryan, M. J., Dhruv, H. D., Gill, S., Eichhoff, O. M., Seashore-Ludlow, B., Kaffenberger, S. D., Eaton, J. K., Shimada, K., Aguirre, A. J., Viswanathan, S. R., Chattopadhyay, S., and 28 others. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547: 453-457, 2017. [PubMed: 28678785] [Full Text: https://doi.org/10.1038/nature23007]
Williams, T. M., Montoya, G., Wu, Y., Eddy, R. L., Byers, M. G., Shows, T. B. The TCF8 gene encoding a zinc finger protein (Nil-2-a) resides on human chromosome 10p11.2. Genomics 14: 194-196, 1992. [PubMed: 1427828] [Full Text: https://doi.org/10.1016/s0888-7543(05)80307-6]
Williams, T. M., Moolten, D., Burlein, J., Romano, J., Bhaerman, R., Godillot, A., Mellon, M., Rauscher, F. J., III, Kant, J. A. Identification of a zinc finger protein that inhibits IL-2 gene expression. Science 254: 1791-1794, 1991. [PubMed: 1840704] [Full Text: https://doi.org/10.1126/science.1840704]