# TWIST1

## Overview
TWIST1 is a gene that encodes the twist family bHLH transcription factor 1, a basic helix-loop-helix (bHLH) transcription factor. This protein is integral to various biological processes, including embryonic development, cell differentiation, and cancer progression. As a transcription factor, TWIST1 regulates gene expression by binding to E-box sequences in DNA, often forming homodimers or heterodimers with other bHLH proteins, such as E2A, to modulate its activity (Miraoui2010Pivotal; Bouard2013Interhelical). The protein's structure, characterized by its bHLH domain, is crucial for its DNA-binding and dimerization capabilities, which are essential for its function in processes like epithelial-mesenchymal transition (EMT) and mesoderm specification (Maia2012Computational; Fan2020TWIST1). Mutations in TWIST1 are linked to Saethre-Chotzen syndrome and various cancers, underscoring its clinical significance in both developmental disorders and oncogenesis (Qin2011Normal; Kress2005Saethre–Chotzen).

## Structure
The TWIST1 protein is a basic helix-loop-helix (bHLH) transcription factor that plays a crucial role in embryonic development and cancer progression. Its primary structure includes a bHLH domain, which is essential for DNA binding and dimerization (Bouard2013Interhelical; Maia2012Computational). The bHLH domain consists of two amphipathic α-helices separated by an interhelical loop, which is critical for the protein's function and stability (Bouard2013Interhelical; Maia2012Computational).

TWIST1 can form homodimers or heterodimers with other bHLH proteins, such as E2A, which influences its DNA-binding efficiency and stability (Bouard2013Interhelical; Maia2012Computational). The choice of dimerization partner affects the structural conformation of the interhelical loops, which are important for maintaining the TWIST1-DNA complex (Bouard2013Interhelical).

Mutations within the bHLH domain, such as R118C, S144R, and K145E, can alter the charge and volume of residue side chains, impacting the protein's DNA-binding capacity and structural stability (Maia2012Computational). These mutations are associated with Saethre-Chotzen syndrome, highlighting the importance of the bHLH domain in TWIST1's function (Maia2012Computational).

## Function
The TWIST1 gene encodes a basic helix-loop-helix (bHLH) transcription factor that plays a critical role in the development and differentiation of mesenchymal cells into various cell types, including chondrocytes, osteoblasts, and adipocytes (Miraoui2010Pivotal). TWIST1 functions by forming homodimers and heterodimers with E proteins, binding to E-box sequences in the DNA of target genes (Miraoui2010Pivotal). This dimerization is crucial for regulating gene networks that control cell differentiation, particularly in processes like epithelial-mesenchymal transition (EMT) and mesoderm specification (Fan2020TWIST1).

In osteoblast differentiation, TWIST1 acts as a molecular switch, influencing the formation of homo- and heterodimers with proteins such as E12 and Id, which affects the regulation of fibroblast growth factor receptors (Fgfrs), particularly Fgfr2 (Franco2010Redundant). TWIST1 homodimers promote osteoblast maturation, while heterodimers maintain cells in a preosteoblast state (Franco2010Redundant). TWIST1 also modulates the function of the transcription factor Runx2, a master regulator of osteogenic genes, by inhibiting its DNA binding ability (Franco2010Redundant).

TWIST1 is also involved in adipocyte differentiation by modulating FGFR2 signaling, which negatively controls adipogenesis (Miraoui2010Pivotal). Its expression in adipose tissue is linked to energy homeostasis, indicating broader physiological roles (Miraoui2010Pivotal). Overall, TWIST1 is essential for maintaining the balance between cell proliferation and differentiation, ensuring proper development and function in various tissues.

## Clinical Significance
Mutations in the TWIST1 gene are associated with Saethre-Chotzen syndrome (SCS), an autosomal dominant disorder characterized by craniosynostosis, facial dysmorphism, and limb abnormalities. These mutations often result in haploinsufficiency, leading to premature fusion of cranial sutures due to increased osteogenic precursor cell proliferation and altered expression of genes like Runx2 and FGFR2 (Miraoui2010Pivotal; Qin2011Normal). SCS is also linked to specific phenotypic features such as ear length below normal, interdigital webbing, and intracranial hypertension (Kress2005Saethre–Chotzen).

Alterations in TWIST1 expression are implicated in various cancers, including breast, prostate, and gastric cancers. TWIST1 overexpression is associated with enhanced epithelial-mesenchymal transition (EMT), promoting cancer cell migration and metastasis. In prostate cancer, high TWIST1 levels correlate with bone metastasis and reduced drug sensitivity (Qin2011Normal). In gastric cancer, TWIST1 overexpression is linked to increased migration and invasion abilities (Qin2011Normal).

TWIST1 also plays a role in vascular diseases, particularly coronary artery disease (CAD) and stroke. Its expression is upregulated in atherosclerotic lesions, influencing smooth muscle cell phenotype and proliferation, which contributes to disease progression (Nurnberg2020Genomic).

## Interactions
TWIST1 is a transcription factor that participates in various protein-protein interactions, influencing its role in cellular processes. It interacts with the NF-κB subunit RELA through its WR domain, which is crucial for the upregulation of interleukin-8 (IL-8), an inflammatory cytokine. This interaction is significant for cancer metastasis and drug resistance, as it facilitates the epithelial to mesenchymal transition (EMT) in cancer cells (Roberts2017Disruption).

TWIST1 also forms a complex with the E12 protein, a member of the E2A family of transcription factors. The R154P point mutation in TWIST1 disrupts its dimerization with E12, affecting the stability and DNA binding of the TWIST1/E12 complex. This mutation alters the hydrogen bond interactions and decreases the free energy of binding, impacting the complex's ability to bind to E-box sequences in DNA (Bouard2017Destabilization).

Additionally, TWIST1 interacts with the programmed cell death protein 4 (PDCD4), which inhibits TWIST1's transcriptional activity by binding to its DNA binding domain. This interaction reduces TWIST1's ability to transactivate target genes, such as YB-1, thereby suppressing cancer cell growth (Shiota2009Programmed).


## References


[1. (Franco2010Redundant) H. L. Franco, J. Casasnovas, J. R. Rodriguez-Medina, and C. L. Cadilla. Redundant or separate entities?–roles of twist1 and twist2 as molecular switches during gene transcription. Nucleic Acids Research, 39(4):1177–1186, October 2010. URL: http://dx.doi.org/10.1093/nar/gkq890, doi:10.1093/nar/gkq890. This article has 204 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkq890)

[2. (Bouard2017Destabilization) Charlotte Bouard, Raphael Terreux, Agnès Tissier, Laurent Jacqueroud, Arnaud Vigneron, Stéphane Ansieau, Alain Puisieux, and Léa Payen. Destabilization of the twist1/e12 complex dimerization following the r154p point-mutation of twist1: an in silico approach. BMC Structural Biology, May 2017. URL: http://dx.doi.org/10.1186/s12900-017-0076-x, doi:10.1186/s12900-017-0076-x. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12900-017-0076-x)

[3. (Kress2005Saethre–Chotzen) Wolfram Kress, Christian Schropp, Gabriele Lieb, Birgit Petersen, Maria Büsse-Ratzka, Jürgen Kunz, Edeltraut Reinhart, Wolf-Dieter Schäfer, Johanna Sold, Florian Hoppe, Jan Pahnke, Andreas Trusen, Niels Sörensen, Jürgen Krauss, and Hartmut Collmann. Saethre–chotzen syndrome caused by twist 1 gene mutations: functional differentiation from muenke coronal synostosis syndrome. European Journal of Human Genetics, 14(1):39–48, October 2005. URL: http://dx.doi.org/10.1038/sj.ejhg.5201507, doi:10.1038/sj.ejhg.5201507. This article has 166 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/sj.ejhg.5201507)

[4. (Shiota2009Programmed) Masaki Shiota, Hiroto Izumi, Akihide Tanimoto, Mayu Takahashi, Naoya Miyamoto, Eiji Kashiwagi, Akihiko Kidani, Gen Hirano, Daisuke Masubuchi, Yasushi Fukunaka, Yoshihiro Yasuniwa, Seiji Naito, Shigeru Nishizawa, Yasuyuki Sasaguri, and Kimitoshi Kohno. Programmed cell death protein 4 down-regulates y-box binding protein-1 expression via a direct interaction with twist1 to suppress cancer cell growth. Cancer Research, 69(7):3148–3156, April 2009. URL: http://dx.doi.org/10.1158/0008-5472.CAN-08-2334, doi:10.1158/0008-5472.can-08-2334. This article has 161 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1158/0008-5472.CAN-08-2334)

[5. (Nurnberg2020Genomic) Sylvia T. Nurnberg, Marie A. Guerraty, Robert C. Wirka, H. Shanker Rao, Milos Pjanic, Scott Norton, Felipe Serrano, Ljubica Perisic, Susannah Elwyn, John Pluta, Wei Zhao, Stephanie Testa, YoSon Park, Trieu Nguyen, Yi-An Ko, Ting Wang, Ulf Hedin, Sanjay Sinha, Yoseph Barash, Christopher D. Brown, Thomas Quertermous, and Daniel J. Rader. Genomic profiling of human vascular cells identifies twist1 as a causal gene for common vascular diseases. PLOS Genetics, 16(1):e1008538, January 2020. URL: http://dx.doi.org/10.1371/journal.pgen.1008538, doi:10.1371/journal.pgen.1008538. This article has 40 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1371/journal.pgen.1008538)

[6. (Roberts2017Disruption) Cai M. Roberts, Sophia A. Shahin, Joana Loeza, Thanh H. Dellinger, John C. Williams, and Carlotta A. Glackin. Disruption of twist1-rela binding by mutation and competitive inhibition to validate the twist1 wr domain as a therapeutic target. BMC Cancer, March 2017. URL: http://dx.doi.org/10.1186/s12885-017-3169-9, doi:10.1186/s12885-017-3169-9. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12885-017-3169-9)

[7. (Fan2020TWIST1) Xiaochen Fan, Ashley J. Waardenberg, Madeleine Demuth, Pierre Osteil, Jane Q. J. Sun, David A. F. Loebel, Mark Graham, Patrick P. L. Tam, and Nicolas Fossat. Twist1 homodimers and heterodimers orchestrate lineage-specific differentiation. Molecular and Cellular Biology, May 2020. URL: http://dx.doi.org/10.1128/MCB.00663-19, doi:10.1128/mcb.00663-19. This article has 27 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/MCB.00663-19)

[8. (Miraoui2010Pivotal) Hichem Miraoui and Pierre J. Marie. Pivotal role of twist in skeletal biology and pathology. Gene, 468(1–2):1–7, November 2010. URL: http://dx.doi.org/10.1016/j.gene.2010.07.013, doi:10.1016/j.gene.2010.07.013. This article has 96 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.gene.2010.07.013)

[9. (Bouard2013Interhelical) Charlotte Bouard, Raphael Terreux, Jennifer Hope, Julie Anne Chemelle, Alain Puisieux, Stéphane Ansieau, and Léa Payen. Interhelical loops within the bhlh domain are determinant in maintaining twist1–dna complexes. Journal of Biomolecular Structure and Dynamics, 32(2):226–241, March 2013. URL: http://dx.doi.org/10.1080/07391102.2012.762722, doi:10.1080/07391102.2012.762722. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.1080/07391102.2012.762722)

[10. (Qin2011Normal) Qian Qin, Young Xu, Tao He, Chunlin Qin, and Jianming Xu. Normal and disease-related biological functions of twist1 and underlying molecular mechanisms. Cell Research, 22(1):90–106, August 2011. URL: http://dx.doi.org/10.1038/cr.2011.144, doi:10.1038/cr.2011.144. This article has 530 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/cr.2011.144)

[11. (Maia2012Computational) Amanda M Maia, João HM da Silva, André L Mencalha, Ernesto R Caffarena, and Eliana Abdelhay. Computational modeling of the bhlh domain of the transcription factor twist1 and r118c, s144r and k145e mutants. BMC Bioinformatics, July 2012. URL: http://dx.doi.org/10.1186/1471-2105-13-184, doi:10.1186/1471-2105-13-184. This article has 28 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/1471-2105-13-184)