# SALL4

## Overview
SALL4 is a gene that encodes the spalt like transcription factor 4, a zinc finger transcription factor involved in the regulation of gene expression and maintenance of pluripotency in embryonic stem cells. The SALL4 protein plays a critical role in various biological processes, including embryogenesis, organogenesis, and hematopoiesis, by interacting with other key transcription factors and regulatory proteins. Mutations in the SALL4 gene are associated with several developmental disorders, and aberrant expression of this gene is implicated in various cancers, highlighting its importance in both normal development and disease (Lim2008Sall4; Tatetsu2016SALL4). As a transcription factor, SALL4 is crucial for maintaining the balance between stem cell renewal and differentiation, making it a significant focus of research in stem cell biology and oncology (Wu2014Identification; Yang2008Genome-wide).

## Structure
SALL4 is a transcription factor characterized by multiple C2H2 zinc finger motifs, which are crucial for its DNA-binding function and transcription regulation (Wu2014Identification). The protein also features a glutamine-rich region important for protein-protein interactions and a conserved twelve-amino-acid domain at the N-terminal region responsible for the repression activity of SALL proteins (Álvarez2021SALL). This repression is mediated by an interaction with the Nucleosome Remodeling and Deacetylase (NuRD) complex. 

SALL4 lacks the fourth zinc finger motif (ZF4) found in other SALL proteins, suggesting a unique structural and functional role (Álvarez2021SALL). Additionally, SALL4 includes nuclear localization sequences (NLS) that are essential for its function within the nucleus (Wu2014Identification; Álvarez2021SALL). The protein's structure is detailed with exon representation and protein length for each isoform, indicating the complexity and variability within the SALL4 protein itself (Álvarez2021SALL).

The primary structure of SALL4 includes specific sequences such as the NLS within amino acids 50-109, specifically the sequence 64 KRLR 67, which matches the canonical NLS motif and is crucial for the protein's interaction with importin-α, mediating its transport through the nuclear pore complex (Wu2014Identification). The secondary, tertiary, and quaternary structures of SALL4 are not detailed in the provided sources.

## Function
SALL4 is a zinc finger transcription factor that plays a pivotal role in maintaining the pluripotency and self-renewal capabilities of embryonic stem cells (ESCs). It is part of a core transcriptional network that includes interactions with other key pluripotency factors such as Oct4, Sox2, and Nanog. These interactions are crucial for maintaining the undifferentiated state of ESCs, as SALL4 can co-occupy gene promoters with these factors, regulating gene expression essential for stem cell properties (Lim2008Sall4; Yang2008Genome-wide).

In addition to its role in ESCs, SALL4 is essential for normal human hematopoiesis, particularly in CD34+ hematopoietic stem/progenitor cells (HSC/HPCs). It regulates genes important for hematopoietic differentiation and self-renewal, including HOXA9, RUNX1, and PTEN. The down-regulation of SALL4 in these cells impairs their myeloid colony-forming abilities and in vivo engraftment, highlighting its critical function in blood formation (gao2013sall4).

SALL4 also influences organogenesis, notably in the development of limbs and the hematopoietic system. Its activity is crucial across various tissues, underscoring its role in both embryonic development and maintaining stem cell populations in adults (Lim2008Sall4).

## Clinical Significance
Mutations in the SALL4 gene are linked to several autosomal dominant disorders, including Okihiro syndrome, also known as Duane-radial ray syndrome, which features limb deformities and loss of eye movement. Other related syndromes include acro-renal-ocular syndrome and Instituto Venezolano de Investigaciones Cientificas syndrome, which present with a range of symptoms such as hand malformations, eye movement disorders, hearing impairment, renal abnormalities, and facial asymmetry (Tatetsu2016SALL4; Nicolè2017Oncofetal).

In cancer, alterations in SALL4 expression are significant. It is constitutively expressed in acute myeloid leukemia (AML) and other hematopoietic malignancies, where it plays a role in leukemogenesis. High SALL4 expression is associated with poor prognosis in AML, aggressive malignant behavior, and resistance to chemotherapy in various cancers, including lung, gastric, and colorectal cancers (Wang2024SALL4; Farawela2019Expression; Cui2006Differential). SALL4's interaction with crucial signaling pathways like Wnt/β-catenin, which is involved in the self-renewal properties of hematopoietic stem cells, underscores its role in the progression of chronic myeloid leukemia (CML) and its blast phase (Ma2006SALL4).

These findings highlight the dual role of SALL4 in developmental disorders and oncogenesis, making it a potential target for therapeutic intervention in both congenital diseases and cancer.

## Interactions
SALL4 interacts with a variety of proteins and complexes to regulate gene expression and maintain cellular functions. It binds to the NuRD complex, LSD1, and DNMTs, functioning as a transcriptional repressor (Tatetsu2016SALL4). Additionally, SALL4 forms complexes with transcriptional regulators like MLL and β-catenin to activate gene expression (Tatetsu2016SALL4). In embryonic stem cells, SALL4 interacts with key pluripotency factors such as Oct4, Nanog, and Sox2, sustaining stem cell properties (Tatetsu2016SALL4). It also plays a role in the DNA damage response by interacting with the Mre11-Rad50-Nbs1 complex and stabilizing it, crucial for the recruitment and activation of ATM at sites of DNA damage (Tatetsu2016SALL4). 

SALL4's interaction with Cyclin D1, identified through a mouse embryonic prey library, involves the C-terminal 238 amino acids of SALL4, which include the carboxy-terminal double zinc finger domain, crucial for binding (Böhm2007Synergistic). This interaction is confirmed by co-immunoprecipitation studies and is significant for its role in transcriptional repression (Böhm2007Synergistic). Furthermore, SALL4 and Cyclin D1 co-localize in the nucleus, suggesting a specific function within this cellular compartment (Böhm2007Synergistic). 

These interactions underline the multifaceted role of SALL4 in regulating gene expression and cellular processes across different biological contexts and diseases.


## References


[1. (Lim2008Sall4) Chin Yan Lim, Wai-Leong Tam, Jinqiu Zhang, Haw Siang Ang, Hui Jia, Leonard Lipovich, Huck-Hui Ng, Chia-Lin Wei, Wing Kin Sung, Paul Robson, Henry Yang, and Bing Lim. Sall4 regulates distinct transcription circuitries in different blastocyst-derived stem cell lineages. Cell Stem Cell, 3(5):543–554, November 2008. URL: http://dx.doi.org/10.1016/j.stem.2008.08.004, doi:10.1016/j.stem.2008.08.004. (192 citations) 10.1016/j.stem.2008.08.004](https://doi.org/10.1016/j.stem.2008.08.004)

[2. (Wang2024SALL4) Tairan Wang, Yan Jin, Mengyao Wang, Boya Chen, Jinyu Sun, Jiaying Zhang, Hui Yang, Xinyao Deng, Xingyue Cao, Lidong Wang, and Yuanyuan Tang. Sall4 in gastrointestinal tract cancers: upstream and downstream regulatory mechanisms. Molecular Medicine, April 2024. URL: http://dx.doi.org/10.1186/s10020-024-00812-z, doi:10.1186/s10020-024-00812-z. (0 citations) 10.1186/s10020-024-00812-z](https://doi.org/10.1186/s10020-024-00812-z)

[3. (Farawela2019Expression) Hala M. Farawela, Hamdy M. Zawam, Hanan A. Al-Wakeel, Mona H. El-Nagdy, Fatma A. El-Refaey, and Hala A. Abdel-Rahman. Expression pattern and prognostic implication of sall4 gene in myeloid leukemias: a case-control study. Scandinavian Journal of Clinical and Laboratory Investigation, 79(1–2):65–70, January 2019. URL: http://dx.doi.org/10.1080/00365513.2018.1555854, doi:10.1080/00365513.2018.1555854. (1 citations) 10.1080/00365513.2018.1555854](https://doi.org/10.1080/00365513.2018.1555854)

[4. (Yang2008Genome-wide) Jianchang Yang, Li Chai, Taylor C. Fowles, Zaida Alipio, Dan Xu, Louis M. Fink, David C. Ward, and Yupo Ma. Genome-wide analysis reveals sall4 to be a major regulator of pluripotency in murine-embryonic stem cells. Proceedings of the National Academy of Sciences, 105(50):19756–19761, December 2008. URL: http://dx.doi.org/10.1073/pnas.0809321105, doi:10.1073/pnas.0809321105. (233 citations) 10.1073/pnas.0809321105](https://doi.org/10.1073/pnas.0809321105)

[5. (Ma2006SALL4) Y. Ma, W. Cui, J. Yang, J. Qu, C. Di, H. M. Amin, R. Lai, J. Ritz, D. S. Krause, and L. Chai. Sall4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (aml) and induces aml in transgenic mice. Blood, 108(8):2726–2735, October 2006. URL: http://dx.doi.org/10.1182/blood-2006-02-001594, doi:10.1182/blood-2006-02-001594. (168 citations) 10.1182/blood-2006-02-001594](https://doi.org/10.1182/blood-2006-02-001594)

[6. (gao2013sall4) Gao, Chong, et al. "SALL4 is a key transcription regulator in normal human hematopoiesis." Transfusion 53.5 (2013): 1037-1049. (57 citations) 10.1111/j.1537-2995.2012.03888](https://doi.org/10.1111/j.1537-2995.2012.03888)

[7. (Wu2014Identification) Meng Wu, Feikun Yang, Zhihua Ren, Yongping Jiang, Yupo Ma, Chang-Yan Chen, and Wei Dai. Identification of the nuclear localization signal of sall4b, a stem cell transcription factor. Cell Cycle, 13(9):1456–1462, March 2014. URL: http://dx.doi.org/10.4161/cc.28418, doi:10.4161/cc.28418. (17 citations) 10.4161/cc.28418](https://doi.org/10.4161/cc.28418)

[8. (Tatetsu2016SALL4) Hiro Tatetsu, Nikki R. Kong, Gao Chong, Giovanni Amabile, Daniel G. Tenen, and Li Chai. Sall4, the missing link between stem cells, development and cancer. Gene, 584(2):111–119, June 2016. URL: http://dx.doi.org/10.1016/j.gene.2016.02.019, doi:10.1016/j.gene.2016.02.019. (123 citations) 10.1016/j.gene.2016.02.019](https://doi.org/10.1016/j.gene.2016.02.019)

[9. (Cui2006Differential) Wei Cui, Nikki R Kong, Yupo Ma, Hesham M Amin, Raymond Lai, and Li Chai. Differential expression of the novel oncogene, sall4, in lymphoma, plasma cell myeloma, and acute lymphoblastic leukemia. Modern Pathology, 19(12):1585–1592, January 2006. URL: http://dx.doi.org/10.1038/modpathol.3800694, doi:10.1038/modpathol.3800694. (69 citations) 10.1038/modpathol.3800694](https://doi.org/10.1038/modpathol.3800694)

[10. (Álvarez2021SALL) Claudia Álvarez, Aracelly Quiroz, Diego Benítez-Riquelme, Elizabeth Riffo, Ariel F. Castro, and Roxana Pincheira. Sall proteins; common and antagonistic roles in cancer. Cancers, 13(24):6292, December 2021. URL: http://dx.doi.org/10.3390/cancers13246292, doi:10.3390/cancers13246292. (20 citations) 10.3390/cancers13246292](https://doi.org/10.3390/cancers13246292)

[11. (Böhm2007Synergistic) Johann Böhm, Frank J. Kaiser, Wiktor Borozdin, Reinhard Depping, and Jürgen Kohlhase. Synergistic cooperation of sall4 and cyclin d1 in transcriptional repression. Biochemical and Biophysical Research Communications, 356(3):773–779, May 2007. URL: http://dx.doi.org/10.1016/j.bbrc.2007.03.050, doi:10.1016/j.bbrc.2007.03.050. (32 citations) 10.1016/j.bbrc.2007.03.050](https://doi.org/10.1016/j.bbrc.2007.03.050)

[12. (Nicolè2017Oncofetal) Lorenzo Nicolè, Tiziana Sanavia, Nicola Veronese, Rocco Cappellesso, Claudio Luchini, Paolo Dabrilli, and Ambrogio Fassina. Oncofetal gene sall4 and prognosis in cancer: a systematic review with meta-analysis. Oncotarget, 8(14):22968–22979, February 2017. URL: http://dx.doi.org/10.18632/oncotarget.14952, doi:10.18632/oncotarget.14952. (34 citations) 10.18632/oncotarget.14952](https://doi.org/10.18632/oncotarget.14952)