# TLE1

## Overview
TLE1, or Transducin-Like Enhancer of split 1, is a gene that encodes the protein TLE family member 1, a transcriptional corepressor involved in various cellular processes. This protein is a part of the Groucho/TLE family, known for its role in repressing gene transcription through interactions with multiple transcription factors. TLE1 is characterized by its ability to modulate gene expression by forming complexes with other proteins and influencing histone modifications, thereby impacting processes such as cell growth, development, and differentiation. The protein itself is not a kinase, receptor, or transmembrane protein but functions primarily in the nucleus to regulate gene transcription. Its involvement extends to various biological pathways and has significant implications in health and disease, including cancer, neurodevelopmental disorders, and inflammatory responses (Ali2010Transcriptional; Yu2022Roles).

## Structure
The TLE1 protein, a member of the Groucho/TLE family, exhibits a complex molecular structure integral to its function as a transcriptional corepressor. The protein is characterized by several evolutionarily conserved domains that contribute to its structural and functional diversity.

The amino-terminal Q domain of TLE1 contains two amphipathic α-helices, AH1 and AH2, which are crucial for oligomerization and protein-protein interactions. This domain facilitates the tetramerization of TLE proteins, essential for their transcriptional repression activity (Jennings2008The; Yu2022Roles).

Central to TLE1's structure is the highly conserved carboxy-terminal WD-repeat domain. This domain forms a seven-bladed β-propeller structure, which plays a pivotal role in mediating interactions with various transcription factors through peptide motifs such as WRPW and the 'eh1' motif (FxIxxIL) (Jennings2008The).

Posttranslational modifications, including phosphorylation and potential poly(ADP-ribosyl)ation, significantly influence TLE1's function. These modifications are facilitated by interactions within protein complexes that include enzymes like poly(ADP-ribose) polymerase 1 (PARP-1) (Jennings2008The).

Additionally, splice variant isoforms of TLE1, such as TLE1DGP which lacks the GP domain, suggest alternative functional roles and regulatory mechanisms within different cellular contexts (Hentschke2003Identification). These isoforms and their specific domain compositions contribute to the diverse functional capabilities of TLE1 in transcriptional regulation.

## Function
TLE1 (Transducin-Like Enhancer of split 1) functions as a transcriptional corepressor in healthy human cells, playing a pivotal role in the regulation of ribosomal RNA (rRNA) gene transcription. It forms a complex with the osteogenic transcription factor Runx2 and the Pol I transcription factor UBF during both mitosis and interphase, occupying nucleolar organizing regions (NORs) and influencing histone modifications. This interaction is crucial for the recruitment of TLE1 to rDNA repeats, where it suppresses gene expression by modulating histone acetylation, specifically reducing the acetylation levels of histones H3 and H4, markers of active transcription (Ali2010Transcriptional).

The repression of rRNA gene transcription by TLE1 is significant as it links the regulation of rRNA gene transcription to cell growth and protein synthesis. In the absence of TLE1, there is an increase in pre-rRNA levels, indicating enhanced Pol I-mediated rRNA gene transcription, which results in increased global protein synthesis and cell growth. This underscores TLE1's role in maintaining cellular homeostasis by regulating the rate of protein synthesis and cell proliferation through its repressive actions on rRNA gene transcription (Ali2010Transcriptional).

## Clinical Significance
TLE1 (Transducin-Like Enhancer of split 1) is implicated in various diseases, primarily through mutations, altered expression levels, or disruptions in its normal interactions. In cancer, TLE1 expression levels and interactions significantly influence tumor progression and prognosis. It is highly expressed in synovial sarcoma, serving as a sensitive and specific diagnostic marker (Yu2022Roles). Conversely, in hematologic malignancies like acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), TLE1 expression is often epigenetically silenced through hypermethylation of its gene promoter, which contributes to tumorigenesis (Fraga2008Epigenetic). Additionally, TLE1 mutations or reduced expression are linked to the pathogenesis of inflammatory bowel disease and hepatic ischemia/reperfusion injury, highlighting its role in inflammatory responses (Yu2022Roles).

In neurodevelopmental disorders, a missense mutation in TLE1 has been associated with postnatal microcephaly and other severe neurological symptoms, resembling FOXG1 syndrome. This mutation leads to decreased cell proliferation and delayed mitosis in affected individuals (Cavallin2018TLE1). These findings underscore the critical role of TLE1 not only in tumorigenesis but also in the development and proper functioning of the nervous system, further emphasizing its clinical significance across a spectrum of diseases.

## Interactions
TLE1 (Transducin-Like Enhancer of split 1) interacts with a variety of transcription factors, influencing gene expression through its role as a transcriptional corepressor. It forms complexes with LEF-1 and AML proteins (AML1 and AML2), which are crucial for its function in repressing transcription in the Wnt/Wg and hematopoiesis signaling pathways. The interaction with LEF-1 is particularly significant in inhibiting LEF-1:β-catenin-mediated transcriptional activation, as TLE1 binds directly to LEF-1 but not to β-catenin (Levanon1998Transcriptional). 

Additionally, TLE1 interacts with FoxG1, a relationship critical for neuronal survival. This interaction is mediated by the carboxyl-terminal WD40R domain of TLE1 and is antagonized by AES and Grg6, which can sequester TLE1 away from FoxG1, leading to neuronal death (Dastidar2012Transducin-like). 

TLE1 also binds to the Qin protein, enhancing Qin-mediated transformation of chicken embryo fibroblasts. This interaction does not require Qin's oligomerization, which is atypical compared to other transcription factors that must oligomerize to bind their respective corepressors (Sonderegger2003Binding).

These interactions highlight TLE1's versatile role in modulating transcriptional repression across different cellular contexts and signaling pathways.


## References


[1. (Levanon1998Transcriptional) Ditsa Levanon, Robert E. Goldstein, Yael Bernstein, Hua Tang, Dalia Goldenberg, Stefano Stifani, Ze’ev Paroush, and Yoram Groner. Transcriptional repression by aml1 and lef-1 is mediated by the tle/groucho corepressors. Proceedings of the National Academy of Sciences, 95(20):11590–11595, September 1998. URL: http://dx.doi.org/10.1073/pnas.95.20.11590, doi:10.1073/pnas.95.20.11590. (593 citations) 10.1073/pnas.95.20.11590](https://doi.org/10.1073/pnas.95.20.11590)

[2. (Jennings2008The) Barbara H Jennings and David Ish-Horowicz. The groucho/tle/grg family of transcriptional co-repressors. Genome Biology, 9(1):205, 2008. URL: http://dx.doi.org/10.1186/gb-2008-9-1-205, doi:10.1186/gb-2008-9-1-205. (196 citations) 10.1186/gb-2008-9-1-205](https://doi.org/10.1186/gb-2008-9-1-205)

[3. (Ali2010Transcriptional) Syed A. Ali, Sayyed K. Zaidi, Jason R. Dobson, Abdul R. Shakoori, Jane B. Lian, Janet L. Stein, Andre J. van Wijnen, and Gary S. Stein. Transcriptional corepressor tle1 functions with runx2 in epigenetic repression of ribosomal rna genes. Proceedings of the National Academy of Sciences, 107(9):4165–4169, February 2010. URL: http://dx.doi.org/10.1073/pnas.1000620107, doi:10.1073/pnas.1000620107. (57 citations) 10.1073/pnas.1000620107](https://doi.org/10.1073/pnas.1000620107)

[4. (Sonderegger2003Binding) Corinna K Sonderegger and Peter K Vogt. Binding of the corepressor tle1 to qin enhances qin-mediated transformation of chicken embryo fibroblasts. Oncogene, 22(12):1749–1757, March 2003. URL: http://dx.doi.org/10.1038/sj.onc.1206308, doi:10.1038/sj.onc.1206308. (34 citations) 10.1038/sj.onc.1206308](https://doi.org/10.1038/sj.onc.1206308)

[5. (Cavallin2018TLE1) Mara Cavallin, Camille Maillard, Marie Hully, Marion Philbert, Nathalie Boddaert, Madeline Louise Reilly, Patrick Nitschké, Amandine Bery, and Nadia Bahi-Buisson. Tle1, a key player in neurogenesis, a new candidate gene for autosomal recessive postnatal microcephaly. European Journal of Medical Genetics, 61(12):729–732, December 2018. URL: http://dx.doi.org/10.1016/j.ejmg.2018.05.002, doi:10.1016/j.ejmg.2018.05.002. (9 citations) 10.1016/j.ejmg.2018.05.002](https://doi.org/10.1016/j.ejmg.2018.05.002)

[6. (Fraga2008Epigenetic) Mario F. Fraga, Maria Berdasco, Esteban Ballestar, Santiago Ropero, Pilar Lopez-Nieva, Lidia Lopez-Serra, José I. Martín-Subero, Maria J. Calasanz, Isabel Lopez de Silanes, Fernando Setien, Sara Casado, Agustin F. Fernandez, Reiner Siebert, Stefano Stifani, and Manel Esteller. Epigenetic inactivation of the groucho homologue gene tle1 in hematologic malignancies. Cancer Research, 68(11):4116–4122, June 2008. URL: http://dx.doi.org/10.1158/0008-5472.can-08-0085, doi:10.1158/0008-5472.can-08-0085. (40 citations) 10.1158/0008-5472.can-08-0085](https://doi.org/10.1158/0008-5472.can-08-0085)

[7. (Hentschke2003Identification) Moritz Hentschke and Uwe Borgmeyer. Identification of pnrc2 and tle1 as activation function-1 cofactors of the orphan nuclear receptor errγ. Biochemical and Biophysical Research Communications, 312(4):975–982, December 2003. URL: http://dx.doi.org/10.1016/j.bbrc.2003.11.025, doi:10.1016/j.bbrc.2003.11.025. (42 citations) 10.1016/j.bbrc.2003.11.025](https://doi.org/10.1016/j.bbrc.2003.11.025)

[8. (Yu2022Roles) Guiping Yu, Yiqi Chen, Yuwen Hu, Yan Zhou, Xiaoling Ding, and Xiaorong Zhou. Roles of transducin-like enhancer of split (tle) family proteins in tumorigenesis and immune regulation. Frontiers in Cell and Developmental Biology, November 2022. URL: http://dx.doi.org/10.3389/fcell.2022.1010639, doi:10.3389/fcell.2022.1010639. (6 citations) 10.3389/fcell.2022.1010639](https://doi.org/10.3389/fcell.2022.1010639)

[9. (Dastidar2012Transducin-like) Somasish Ghosh Dastidar, Sriram Narayanan, Stefano Stifani, and Santosh R. D’Mello. Transducin-like enhancer of split-1 (tle1) combines with forkhead box protein g1 (foxg1) to promote neuronal survival. Journal of Biological Chemistry, 287(18):14749–14759, April 2012. URL: http://dx.doi.org/10.1074/jbc.m111.328336, doi:10.1074/jbc.m111.328336. (29 citations) 10.1074/jbc.m111.328336](https://doi.org/10.1074/jbc.m111.328336)