Alternative titles; symbols
HGNC Approved Gene Symbol: TLE1
Cytogenetic location: 9q21.32 Genomic coordinates (GRCh38): 9:81,583,683-81,689,547 (from NCBI)
The TLE1 gene encodes a non-DNA-binding transcriptional corepressor that interacts with FOXG1 (164874). TLE1 is highly expressed in postnatal brain (summary by Cavallin et al., 2018).
Stifani et al. (1992) described human homologs of Drosophila groucho protein; these were designated TLE for 'transducin-like enhancer of split.' Miyasaka et al. (1993) reported the cDNA cloning, nucleotide and deduced amino acid sequencing, and tissue-specific expression of mouse and human TLE genes (also known as ESG for 'enhancer of split groucho').
Using the N-terminal activator function-1 (AF1) domain of mouse estrogen-related receptor-gamma (ESRRG; 602969) isoform-2 (ESRRG2) as bait in a yeast 2-hybrid screen of a human brain cDNA library, followed by PCR of a human teratocarcinoma cell line cDNA library, Hentschke and Borgmeyer (2003) cloned full-length TLE1 and a TLE1 splice variant. The deduced full-length protein contains 770 amino acids and has a C-terminal WD40 domain. Northern blot analysis detected TLE1 transcripts of 4.4 and 2.6 kb. Expression was highest in skeletal muscle and liver, moderate in placenta, heart, kidney, and spleen, and weak in all other tissues examined, including brain.
Liu et al. (1996) showed that expression of individual TLE genes correlated with immature epithelial cells that are progressing toward that terminally differentiated state, suggesting a role during epithelial differentiation. In both normal tissues and tissues resulting from incorrect or incomplete maturation events (such as metaplastic and neoplastic transformations), TLE expression was elevated and coincided with 'Notch' (190198) expression, implicating these molecules in the maintenance of the undifferentiated state in epithelial cells.
By coprecipitation analysis, Imai et al. (1998) showed that TLE1 binds to the Runt domain and the C terminus of AML1 (RUNX1; 151385), but not to CBFB (121360), mainly through the SP domain but also through the WD-40 domain of TLE1. Binding of TLE1 to the C terminus of RUNX1 inhibits RUNX1-induced transactivation of the CSF1 receptor (CSF1R; 164770).
Using a protein pull-down assay, Hentschke and Borgmeyer (2003) confirmed interaction between human TLE1 and mouse Esrrg2. Coexpression of TLE1 and Esrrg2 in simian kidney cells resulted in increased reporter gene activity compared with that shown by Esrrg2 alone. Mutation analysis showed that both the AF1 and AF2 domains of Esrrg2 were required for TLE1-dependent transactivation. The WD40 domain of TLE1 was required for interaction with Esrrg2, and the GP and Q domains of TLE1 were important for Esrrg2 coactivation.
Allen et al. (2006) found that transgenic mice with widespread overexpression of Grg1 specifically developed tumors in the lung starting at 1 month of age. Coexpression of Grg5 (AES; 600188) lowered Grg1-induced tumor burden, suggesting a mechanism that is sensitive to levels of long and short Groucho isoforms. Development of lung tumors in Grg1-overexpressing mice was associated with altered status of p53 (TP53; 191170) and upregulation of Erbb1 (EGFR; 131550) and Erbb2 (164870) receptor tyrosine kinases. Examination of GRG1 expression in human lung cancer tissues revealed GRG1 overexpression in a significant number of squamous cell carcinomas and adenocarcinomas. Allen et al. (2006) concluded that GRG1 can act as an oncoprotein in lung.
By mass spectrometric analysis, Higa et al. (2006) identified over 20 WD40 repeat-containing (WDR) proteins that interacted with the CUL4 (see 603137)-DDB1 (600045)-ROC1 (RBX1; 603814) complex, including TLE1, TLE2 (601041), and TLE3 (600190). Sequence alignment revealed that TLE1 and most of the interacting WDR proteins had a centrally positioned WDxR/K submotif. Knockdown studies suggested that the WDR proteins functioned as substrate-specific adaptors for the CUL4-DDB1 complex.
Sweetser et al. (2005) determined that the TLE1 gene contains 19 exons.
By Southern blot analysis of genomic DNA from human/Chinese hamster somatic hybrid cell lines, Miyasaka et al. (1993) mapped the human TLE1 gene to chromosome 9.
Using FISH, Liu et al. (1996) found that the TLE1 and TLE2 (601041) genes are organized in a tandem array on chromosome 19p13.3, in contrast with the mapping of TLE1 to chromosome 9 by Miyasaka et al. (1993). However, Liu et al. (1996) found a TLE-related gene on chromosome 9q22 and concluded that it represents a novel TLE gene or a pseudogene.
Gross (2017) mapped the TLE1 gene to chromosome 9q21.32 based on an alignment of the TLE1 sequence (GenBank BC010100) with the genomic sequence (GRCh38).
Associations Pending Confirmation
For discussion of a possible association between postnatal microcephaly and a severe neurodevelopmental disorder and variation in the TLE1 gene, see 600189.0001.
This variant is classified as a variant of unknown significance because its contribution to postnatal microcephaly and a severe neurodevelopmental disorder has not been confirmed.
In a 6-year-old girl, born of consanguineous Pakistani parents, with postnatal microcephaly (-6 SD) and a severe neurodevelopmental disorder, Cavallin et al. (2018) identified a homozygous c.1651G-A transition (c.1651G-A, NM_001300303.1) in the TLE1 gene, resulting in an asp541-to-asn (D541N) substitution at a highly conserved residue. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a low frequency in the dbSNP, Exome Variant Server, and ExAC databases with a minor allele frequency of 0.0001. Patient fibroblasts showed a significant decrease in mitotic and proliferative indices compared controls, suggesting that the TLE1 variant causes a lengthening of the cell cycle and aborted cell division. The patient had a normal early neonatal course, but developed crying and dyskinesias around 1 month of age. This was followed by profound developmental delay with inability to smile, hold her head up, or follow visually. She had hypotonia, failure to thrive, orofacial dyskinesia necessitating tube feeding, intermittent opisthotonic posturing, and peripheral hypertonia. She did not have seizures, but had myoclonus. Her head circumference decelerated, and brain imaging showed progressive cerebral atrophy with delayed myelination. At age 6, she had spastic quadriplegia and no head control, eye contact, or ability to communicate. Cavallin et al. (2018) noted that the phenotype had some similarities to a phenotype (see 613454) associated with mutation in the FOXG1 gene (164874), and that both genes interact to control neurogenesis and survival in postmitotic neurons.
Allen, T., van Tuyl, M., Iyengar, P., Jothy, S., Post, M., Tsao, M.-S., Lobe, C. G. Grg1 acts as a lung-specific oncogene in a transgenic mouse model. Cancer Res. 66: 1294-1301, 2006. [PubMed: 16452182] [Full Text: https://doi.org/10.1158/0008-5472.CAN-05-1634]
Cavallin, M., Maillard, C., Hully, M., Philbert, M., Boddaert, N., Reilly, M. L., Nitschke, P., Bery, A., Bahi-Buisson, N. TLE1, a key player in neurogenesis, a new candidate gene for autosomal recessive postnatal microcephaly. Europ. J. Med. Genet. 61: 729-732, 2018. [PubMed: 29758293] [Full Text: https://doi.org/10.1016/j.ejmg.2018.05.002]
Gross, M. B. Personal Communication. Baltimore, Md. 1/3/2017.
Hentschke, M., Borgmeyer, U. Identification of PNRC2 and TLE1 as activation function-1 cofactors of the orphan nuclear receptor ERR-gamma. Biochem. Biophys. Res. Commun. 312: 975-982, 2003. [PubMed: 14651967] [Full Text: https://doi.org/10.1016/j.bbrc.2003.11.025]
Higa, L. A., Wu, M., Ye, T., Kobayashi, R., Sun, H., Zhang, H. CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nature Cell Biol. 8: 1277-1283, 2006. [PubMed: 17041588] [Full Text: https://doi.org/10.1038/ncb1490]
Imai, Y., Kurokawa, M., Tanaka, K., Friedman, A. D., Ogawa, S., Mitani, K., Yazaki, Y., Hirai, H. TLE, the human homolog of groucho, interacts with AML1 and acts as a repressor of AML1-induced transactivation. Biochem. Biophys. Res. Commun. 252: 582-589, 1998. [PubMed: 9837750] [Full Text: https://doi.org/10.1006/bbrc.1998.9705]
Liu, Y., Dehni, G., Purcell, K. J., Sokolow, J., Carcangiu, M. L., Artavanis-Tsakonas, S., Stifani, S. Epithelial expression and chromosomal location of human TLE genes: implications for Notch signaling and neoplasia. Genomics 31: 58-64, 1996. [PubMed: 8808280] [Full Text: https://doi.org/10.1006/geno.1996.0009]
Miyasaka, H., Choudhury, B. K., Hou, E. W., Li, S. S.-L. Molecular cloning and expression of mouse and human cDNA encoding AES and ESG proteins with strong similarity to Drosophila enhancer of split groucho protein. Europ. J. Biochem. 216: 343-352, 1993. [PubMed: 8365415] [Full Text: https://doi.org/10.1111/j.1432-1033.1993.tb18151.x]
Stifani, S., Blaumueller, C. M., Redhead, N. J., Hill, R. E., Artavanis-Tsakonas, S. Human homologs of a Drosophila enhancer of split gene product define a novel family of nuclear proteins. Nature Genet. 2: 119-127, 1992. Note: Erratum: Nature Genet. 2: 343 only, 1992. [PubMed: 1303260] [Full Text: https://doi.org/10.1038/ng1092-119]
Sweetser, D. A., Peniket, A. J., Haaland, C., Blomberg, A. A., Zhang, Y., Zaidi, S. T., Dayyani, F., Zhao, Z., Heerema, N. A., Boultwood, J., Dewald, G. W., Paietta, E., Slovak, M. L., Willman, C. L., Wainscoat, J. S., Bernstein, I. D., Daly, S. B. Delineation of the minimal commonly deleted segment and identification of candidate tumor-suppressor genes in del(9q) acute myeloid leukemia. Genes Chromosomes Cancer 44: 279-291, 2005. [PubMed: 16015647] [Full Text: https://doi.org/10.1002/gcc.20236]