# LEF1

## Overview
Lymphoid enhancer binding factor 1 (LEF1) is a gene that encodes a transcription factor belonging to the high-mobility group (HMG) family, which is involved in the regulation of gene expression through the Wnt signaling pathway. The LEF1 protein is characterized by its ability to bind and bend DNA, facilitating the assembly of transcriptional complexes. It plays a pivotal role in various biological processes, including T-cell development, hair follicle formation, and bone development. LEF1 functions as both a transcriptional activator and repressor, depending on the presence of β-catenin, a key component of the Wnt signaling pathway. The protein's interaction with β-catenin is crucial for the transcriptional activation of Wnt-responsive genes, while in the absence of Wnt signals, LEF1 can recruit histone deacetylase activity to maintain gene repression. LEF1's involvement in these processes underscores its significance in maintaining cellular homeostasis and proper organismal development (Hsu1998Modulation; Billin2000βCatenin–Histone; Giese1991DNAbinding).

## Structure
LEF1 (lymphoid enhancer binding factor 1) is a transcription factor characterized by its high-mobility group (HMG) domain, which plays a crucial role in DNA binding and bending. The HMG domain of LEF1 is composed of approximately 85 amino acids and is responsible for inducing a significant bend in the DNA helix, facilitating the assembly of nucleoprotein structures (Giese1992The). This domain interacts primarily with the minor groove of DNA, causing a distortion from the normal B-form geometry (Love2004The).

The LEF1 protein undergoes a disorder-to-order transition upon binding to DNA, with the HMG domain becoming more structured in the DNA-bound state. This transition involves the formation of helices II and III, although helix III is truncated at its C-terminal end (Love2004The). The major hydrophobic core between these helices is formed in the DNA-bound state, contributing to the stability of the protein-DNA complex (Love2004The).

LEF1 also contains a β-catenin binding domain, which is essential for its role in transcriptional regulation within the Wnt signaling pathway. The protein can undergo post-translational modifications such as phosphorylation, which may influence its activity and interactions. Multiple splice variants of LEF1 exist, potentially altering its functional properties (Giese1991DNAbinding).

## Function
LEF1 (lymphoid enhancer binding factor 1) is a transcription factor that plays a crucial role in the Wnt signaling pathway, which is essential for regulating gene expression during development and cell differentiation. In healthy human cells, LEF1 functions primarily in the nucleus, where it interacts with β-catenin to mediate transcriptional activation of Wnt-responsive genes (Hsu1998Modulation). This interaction is vital for the transcriptional response to Wnt signaling, as LEF1 forms a complex with β-catenin that activates gene expression by altering chromatin structure and recruiting transcriptional machinery (Billin2000βCatenin–Histone).

LEF1 is involved in various cellular processes, including T-cell development, hair follicle formation, and bone development. It acts as an architectural transcription factor, introducing a sharp bend in DNA, which facilitates the assembly of transcriptional complexes (Hsu1998Modulation). LEF1 can also function as a transcriptional repressor in the absence of Wnt signals by recruiting histone deacetylase activity, maintaining target genes in a repressed state until Wnt signaling is activated (Billin2000βCatenin–Histone). This dual role of LEF1 in transcriptional regulation underscores its importance in maintaining cellular homeostasis and proper organismal development.

## Clinical Significance
LEF1 (lymphoid enhancer binding factor 1) plays a significant role in various hematological malignancies and other conditions due to its involvement in the Wnt signaling pathway. In cytogenetically normal acute myeloid leukemia (CN-AML), high LEF1 expression is associated with favorable prognostic outcomes, including higher complete remission rates and longer survival times. This expression is linked to the absence of FLT3-ITD mutations and low ERG expression, both favorable molecular characteristics in CN-AML (Metzeler2012High).

In contrast, in T-cell acute lymphoblastic leukemia (T-ALL), LEF1 inactivation, often through microdeletions or sequence alterations, is associated with increased MYC expression and a differentiation arrest in thymocyte development. This inactivation is frequently found alongside other mutations, such as NOTCH1 and PTEN, contributing to the pathogenesis of T-ALL (Gutierrez2010Inactivation).

In adult acute lymphoblastic leukemia (ALL), high LEF1 expression correlates with high-risk factors, such as high white blood cell counts and Philadelphia chromosome positivity, leading to poorer prognostic outcomes (Guo2015Characterization).

LEF1 haploinsufficiency has also been implicated in ectodermal dysplasia, characterized by defects in ectoderm-derived structures like teeth and hair, due to its role in the Wnt/β-catenin pathway (Lévy2020LEF1).

## Interactions
LEF1 interacts with several proteins and nucleic acids, playing a crucial role in transcriptional regulation. It forms a complex with β-catenin, which is essential for its transcriptional activation potential. This interaction allows LEF1 to stimulate transcription from multimerized LEF/TCF binding sites, enhancing gene expression in response to Wnt signaling (Hsu1998Modulation). LEF1 also associates with histone deacetylase 1 (HDAC1) to repress transcription by targeting HDAC-containing corepressor complexes to DNA, leading to hypoacetylation of promoter-proximal histones. This repression is relieved when β-catenin levels rise, dissociating HDAC1 from LEF1 and allowing transcriptional activation (Billin2000βCatenin–Histone).

LEF1 can form phase-separated droplets with β-catenin in vitro, a process influenced by the intrinsically disordered region (IDR) of LEF1, which is crucial for its phase separation and transcriptional activation functions (Zhao2023LEF1). LEF1 also interacts with OTUD7B, a deubiquitinase that promotes its nuclear localization and interaction with β-catenin, thereby activating the Wnt signaling pathway (Lee2023OTUD7B). These interactions highlight LEF1's role as a versatile transcription factor involved in various regulatory mechanisms.


## References


[1. (Lee2023OTUD7B) Yuri Lee, Hai-long Piao, and Jongchan Kim. Otud7b activates wnt signaling pathway through the interaction with lef1. Biomolecules, 13(6):1001, June 2023. URL: http://dx.doi.org/10.3390/biom13061001, doi:10.3390/biom13061001. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/biom13061001)

[2. (Metzeler2012High) Klaus H. Metzeler, Bernhard Heilmeier, Katrin E. Edmaier, Vijay P. S. Rawat, Annika Dufour, Konstanze Döhner, Michaela Feuring-Buske, Jan Braess, Karsten Spiekermann, Thomas Büchner, Maria C. Sauerland, Hartmut Döhner, Wolfgang Hiddemann, Stefan K. Bohlander, Richard F. Schlenk, Lars Bullinger, and Christian Buske. High expression of lymphoid enhancer-binding factor-1 (lef1) is a novel favorable prognostic factor in cytogenetically normal acute myeloid leukemia. Blood, 120(10):2118–2126, September 2012. URL: http://dx.doi.org/10.1182/blood-2012-02-411827, doi:10.1182/blood-2012-02-411827. This article has 52 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1182/blood-2012-02-411827)

[3. (Zhao2023LEF1) Bing Zhao, Zhuoxin Li, Shaoqing Yu, Tingting Li, Wen Wang, Ran Liu, Biyu Zhang, Xiya Fang, Yezhuang Shen, Qiuying Han, Xin Xu, Kai Wang, Weili Gong, Tao Li, Ailing Li, Tao Zhou, Weihua Li, and Teng Li. Lef1 enhances β-catenin transactivation through idr-dependent liquid–liquid phase separation. Life Science Alliance, 6(11):e202302118, September 2023. URL: http://dx.doi.org/10.26508/lsa.202302118, doi:10.26508/lsa.202302118. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.26508/lsa.202302118)

[4. (Billin2000βCatenin–Histone) Andrew N. Billin, Hilary Thirlwell, and Donald E. Ayer. Β-catenin–histone deacetylase interactions regulate the transition of lef1 from a transcriptional repressor to an activator. Molecular and Cellular Biology, 20(18):6882–6890, September 2000. URL: http://dx.doi.org/10.1128/MCB.20.18.6882-6890.2000, doi:10.1128/mcb.20.18.6882-6890.2000. This article has 283 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/MCB.20.18.6882-6890.2000)

[5. (Guo2015Characterization) Xing Guo, Run Zhang, Juan Liu, Min Li, Chunhua Song, Sinisa Dovat, Jianyong Li, and Zheng Ge. Characterization of lef1 high expression and novel mutations in adult acute lymphoblastic leukemia. PLOS ONE, 10(5):e0125429, May 2015. URL: http://dx.doi.org/10.1371/journal.pone.0125429, doi:10.1371/journal.pone.0125429. This article has 44 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0125429)

[6. (Lévy2020LEF1) Jonathan Lévy, Yline Capri, Myriam Rachid, Céline Dupont, Joris R. Vermeesch, Koen Devriendt, Alain Verloes, Anne‐Claude Tabet, and Isabelle Bailleul‐Forestier. Lef1 haploinsufficiency causes ectodermal dysplasia. Clinical Genetics, 97(4):595–600, February 2020. URL: http://dx.doi.org/10.1111/cge.13714, doi:10.1111/cge.13714. This article has 14 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/cge.13714)

[7. (Love2004The) John J. Love, Xiang Li, John Chung, H. Jane Dyson, and Peter E. Wright. The lef-1 high-mobility group domain undergoes a disorder-to-order transition upon formation of a complex with cognate dna. Biochemistry, 43(27):8725–8734, June 2004. URL: http://dx.doi.org/10.1021/bi049591m, doi:10.1021/bi049591m. This article has 57 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/bi049591m)

[8. (Gutierrez2010Inactivation) Alejandro Gutierrez, Takaomi Sanda, Wenxue Ma, Jianhua Zhang, Ruta Grebliunaite, Suzanne Dahlberg, Donna Neuberg, Alexei Protopopov, Stuart S. Winter, Richard S. Larson, Michael J. Borowitz, Lewis B. Silverman, Lynda Chin, Stephen P. Hunger, Catriona Jamieson, Stephen E. Sallan, and A. Thomas Look. Inactivation of lef1 in t-cell acute lymphoblastic leukemia. Blood, 115(14):2845–2851, April 2010. URL: http://dx.doi.org/10.1182/blood-2009-07-234377, doi:10.1182/blood-2009-07-234377. This article has 98 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1182/blood-2009-07-234377)

[9. (Hsu1998Modulation) Shu-Chi Hsu, Juan Galceran, and Rudolf Grosschedl. Modulation of transcriptional regulation by lef-1 in response to wnt-1 signaling and association with β-catenin. Molecular and Cellular Biology, 18(8):4807–4818, August 1998. URL: http://dx.doi.org/10.1128/mcb.18.8.4807, doi:10.1128/mcb.18.8.4807. This article has 310 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.18.8.4807)

[10. (Giese1991DNAbinding) K Giese, A Amsterdam, and R Grosschedl. Dna-binding properties of the hmg domain of the lymphoid-specific transcriptional regulator lef-1. Genes & Development, 5(12b):2567–2578, December 1991. URL: http://dx.doi.org/10.1101/gad.5.12b.2567, doi:10.1101/gad.5.12b.2567. This article has 196 citations.](https://doi.org/10.1101/gad.5.12b.2567)

[11. (Giese1992The) Klaus Giese, Jeffery Cox, and Rudolf Grosschedl. The hmg domain of lymphoid enhancer factor 1 bends dna and facilitates assembly of functional nucleoprotein structures. Cell, 69(1):185–195, April 1992. URL: http://dx.doi.org/10.1016/0092-8674(92)90129-z, doi:10.1016/0092-8674(92)90129-z. This article has 484 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/0092-8674(92)90129-z)