SNAI2

SNAI2
Identifiers
Aliases	SNAI2, SLUG, SLUGH1, SNAIL2, WS2D, snail family transcriptional repressor 2, SLUGH
External IDs	OMIM: 602150; MGI: 1096393; HomoloGene: 31127; GeneCards: SNAI2; OMA:SNAI2 - orthologs
Gene location (Human) Chr. Chromosome 8 (human)[1] Band 8q11.21 Start 48,917,598 bp[1] End 48,921,740 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16 A1|16 10.07 cM Start 14,523,716 bp[2] End 14,527,249 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tibia cartilage tissue stromal cell of endometrium skin of thigh skin of arm skin of hip periodontal fiber mucosa of paranasal sinus tail of epididymis seminal vesicula Top expressed in condyle fossa migratory enteric neural crest cell conjunctival fornix endothelial cell of lymphatic vessel hair follicle vas deferens calvaria maxillary prominence body of femur More reference expression data BioGPS More reference expression data
Gene ontology Molecular function sequence-specific DNA binding DNA binding metal ion binding protein binding nucleic acid binding DNA-binding transcription factor activity, RNA polymerase II-specific DNA-binding transcription repressor activity, RNA polymerase II-specific RNA polymerase II transcription regulatory region sequence-specific DNA binding chromatin binding DNA-binding transcription factor activity transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding E-box binding Cellular component cytoplasm nucleus nucleoplasm Biological process Notch signaling pathway negative regulation of vitamin D receptor signaling pathway regulation of transcription, DNA-templated neural crest cell development negative regulation of keratinocyte proliferation regulation of bicellular tight junction assembly positive regulation of cell migration negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage transcription, DNA-templated cellular response to epidermal growth factor stimulus negative regulation of vitamin D biosynthetic process regulation of chemokine production multicellular organism development negative regulation of chondrocyte differentiation negative regulation of DNA damage response, signal transduction by p53 class mediator regulation of osteoblast differentiation osteoblast differentiation canonical Wnt signaling pathway negative regulation of canonical Wnt signaling pathway negative regulation of cell adhesion mediated by integrin negative regulation of anoikis negative regulation of transcription by RNA polymerase II epithelial to mesenchymal transition epithelial to mesenchymal transition involved in endocardial cushion formation cell migration involved in endocardial cushion formation hearing desmosome disassembly pigmentation epithelium development negative regulation of extrinsic apoptotic signaling pathway in absence of ligand aortic valve morphogenesis negative regulation of cell adhesion involved in substrate-bound cell migration response to radiation cell migration positive regulation of histone acetylation negative regulation of apoptotic process positive regulation of fat cell differentiation white fat cell differentiation roof of mouth development cartilage morphogenesis regulation of branching involved in salivary gland morphogenesis cellular response to ionizing radiation negative regulation of stem cell proliferation Notch signaling involved in heart development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6591 20583 Ensembl ENSG00000019549 ENSMUSG00000022676 UniProt O43623 P97469 RefSeq (mRNA) NM_003068 NM_011415 RefSeq (protein) NP_003059 NP_035545 Location (UCSC) Chr 8: 48.92 – 48.92 Mb Chr 16: 14.52 – 14.53 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Zinc finger protein SNAI2 (also called SLUG) is a transcription factor that in humans is encoded by the SNAI2 gene. It promotes epithelial to mesenchymal transition, differentiation (e.g. in gastrulation), and migration of cells.^[5][6][7]

Function

This gene encodes a member of the Snail superfamily of C2H2-type zinc finger transcription factors. The encoded protein acts as a transcriptional repressor that binds to E-box motifs and is also likely to repress E-cadherin transcription in breast carcinoma. This protein is involved in epithelial-mesenchymal transitions and has antiapoptotic activity. It regulates differentiation and migration of neural crest cells along with other genes (e.g. FOXD3, SOX9 and SOX10, BMPs) in embryonic life. Mutations in this gene may be associated with sporadic cases of neural tube defects.^[7][8]

SNAI2 downregulates expression of E-cadherin in premigratory neural crest cells; thus, SNAI2 induces tightly bound epithelial cells to break into a loose mesenchymal phenotype, allowing gastrulation of mesoderm in the developing embryo.^[9][10] Structurally similar to anti-apoptotic Ces-1 in C. elegans, SLUG is a negative regulator of productive cell death in the developing embryo and adults.^[9][11]

Clinical significance

Widely expressed in human tissues, SLUG is most notably absent in peripheral blood leukocytes, adult liver, and both fetal and adult brain tissues.^[11] SLUG plays a role in breast carcinoma as well as leukemia by downregulation of E-cadherin, which supports mesenchymal phenotype by shifting expression from a Type I to Type II cadherin profile.^[11][12] Maintenance of mesenchymal phenotype enables metastasis of tumor cells, though SLUG is expressed in carcinomas regardless to invasiveness.^[9][10][11] A knockout model using chick embryos has also showed inhibition of mesodermal and neural crest delamination; chick embryo Slug gain of function appears to increase neural crest production.^[9] Mutations in Slug are associated with loss of pregnancy during gastrulation in some animals.^[9]

Interactions

Bone morphogenetic proteins (BMPs) precede expression of SLUG and are suspected as the immediate upstream inducers of gene expression.^[10][13]

Snail2 and PRC2 in Neural Crest Development

During early vertebrate development, SLUG partners with the Polycomb repressive complex 2 (PRC2) to regulate the formation and migration of neural crest cells, a group of cells that contribute to facial structures, nerves, and pigment cells. PRC2, made up of EZH2, EED, and SUZ12, modifies chromatin to silence genes by adding repressive histone marks (H3K27me3). These components are actively expressed in neural and neural crest tissues and are essential for normal development in these regions.^[14]

Experiments showed that loss of EZH2 leads to reduced expression of important neural crest genes such as Snail2, Sox9, and Sox10, impaired cell migration, and craniofacial defects. The researchers also found that Snail2 physically interacts with EZH2, helping to guide PRC2 to specific target genes.^[14]

One key target is E-cadherin, a gene that must be repressed for neural crest cells to undergo epithelial-to-mesenchymal transition (EMT) and migrate. Snail2 and EZH2 were shown to co-bind the E-cadherin promoter, and without EZH2, Snail2 could not silence the gene effectively. This results in failed EMT and reduced cell movement.^[14]

Together, these findings show that Snail2 relies on PRC2 not just to repress target genes, but to carry out the complex choreography of neural crest development.

References

1. GRCh38: Ensembl release 89: ENSG00000019549 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022676 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Rhim H, Savagner P, Thibaudeau G, Thiery JP, Pavan WJ (Jan 1998). "Localization of a neural crest transcription factor, Slug, to mouse chromosome 16 and human chromosome 8". Mammalian Genome. 8 (11): 872–873. doi:10.1007/s003359900601. PMID 9337409. S2CID 2177885.
6. Cohen ME, Yin M, Paznekas WA, Schertzer M, Wood S, Jabs EW (August 1998). "Human SLUG gene organization, expression, and chromosome map location on 8q". Genomics. 51 (3): 468–471. doi:10.1006/geno.1998.5367. PMID 9721220.
7. "Entrez Gene: SNAI2 snail homolog 2 (Drosophila)".
8. Stegmann K, Boecker J, Kosan C, Ermert A, Kunz J, Koch MC (August 1999). "Human transcription factor SLUG: mutation analysis in patients with neural tube defects and identification of a missense mutation (D119E) in the Slug subfamily-defining region". Mutation Research. 406 (2–4): 63–69. doi:10.1016/s1383-5726(99)00002-3. PMID 10479723.
9. Nieto MA (March 2002). "The snail superfamily of zinc-finger transcription factors". Nature Reviews. Molecular Cell Biology. 3 (3): 155–166. doi:10.1038/nrm757. PMID 11994736. S2CID 8330951.
10. Carlson BM (2013). Human Embryology and Developmental Biology (5th ed.). Philadelphia, PA: Elsevier Health Sciences. pp. 101–102, 106, 313, 362, 382. ISBN 978-1-4557-2794-0.
11. Inukai T, Inoue A, Kurosawa H, Goi K, Shinjyo T, Ozawa K, et al. (September 1999). "SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein". Molecular Cell. 4 (3): 343–352. doi:10.1016/S1097-2765(00)80336-6. PMID 10518215.
12. Kalluri R, Weinberg RA (June 2009). "The basics of epithelial-mesenchymal transition". The Journal of Clinical Investigation. 119 (6): 1420–1428. doi:10.1172/jci39104. PMC 2689101. PMID 19487818.
13. Sakai D, Wakamatsu Y (2005). "Regulatory mechanisms for neural crest formation". Cells Tissues Organs. 179 (1–2): 24–35. doi:10.1159/000084506. PMID 15942190. S2CID 1886380.
14. Tien CL, Jones A, Wang H, Gerigk M, Nozell S, Chang C (February 2015). "Snail2/Slug cooperates with Polycomb repressive complex 2 (PRC2) to regulate neural crest development". Development. 142 (4): 722–731. doi:10.1242/dev.111997. PMC 4325378. PMID 25617436.

Further reading

• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Savagner P, Yamada KM, Thiery JP (June 1997). "The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition". The Journal of Cell Biology. 137 (6): 1403–1419. doi:10.1083/jcb.137.6.1403. PMC 2132541. PMID 9182671.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Stegmann K, Boecker J, Kosan C, Ermert A, Kunz J, Koch MC (August 1999). "Human transcription factor SLUG: mutation analysis in patients with neural tube defects and identification of a missense mutation (D119E) in the Slug subfamily-defining region". Mutation Research. 406 (2–4): 63–69. doi:10.1016/S1383-5726(99)00002-3. PMID 10479723.
• Inukai T, Inoue A, Kurosawa H, Goi K, Shinjyo T, Ozawa K, et al. (September 1999). "SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein". Molecular Cell. 4 (3): 343–352. doi:10.1016/S1097-2765(00)80336-6. PMID 10518215.
• Hemavathy K, Guru SC, Harris J, Chen JD, Ip YT (July 2000). "Human Slug is a repressor that localizes to sites of active transcription". Molecular and Cellular Biology. 20 (14): 5087–5095. doi:10.1128/MCB.20.14.5087-5095.2000. PMC 85958. PMID 10866665.
• Hajra KM, Chen DY, Fearon ER (March 2002). "The SLUG zinc-finger protein represses E-cadherin in breast cancer". Cancer Research. 62 (6): 1613–1618. PMID 11912130.
• Sánchez-Martín M, Rodríguez-García A, Pérez-Losada J, Sagrera A, Read AP, Sánchez-García I (December 2002). "SLUG (SNAI2) deletions in patients with Waardenburg disease". Human Molecular Genetics. 11 (25): 3231–3236. doi:10.1093/hmg/11.25.3231. PMID 12444107.
• Kajita M, McClinic KN, Wade PA (September 2004). "Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress". Molecular and Cellular Biology. 24 (17): 7559–7566. doi:10.1128/MCB.24.17.7559-7566.2004. PMC 506998. PMID 15314165.
• Catalano A, Rodilossi S, Rippo MR, Caprari P, Procopio A (November 2004). "Induction of stem cell factor/c-Kit/slug signal transduction in multidrug-resistant malignant mesothelioma cells". The Journal of Biological Chemistry. 279 (45): 46706–46714. doi:10.1074/jbc.M406696200. PMID 15337769.
• Uchikado Y, Natsugoe S, Okumura H, Setoyama T, Matsumoto M, Ishigami S, et al. (February 2005). "Slug Expression in the E-cadherin preserved tumors is related to prognosis in patients with esophageal squamous cell carcinoma". Clinical Cancer Research. 11 (3): 1174–1180. doi:10.1158/1078-0432.1174.11.3. PMID 15709186.
• Tripathi MK, Misra S, Khedkar SV, Hamilton N, Irvin-Wilson C, Sharan C, et al. (April 2005). "Regulation of BRCA2 gene expression by the SLUG repressor protein in human breast cells". The Journal of Biological Chemistry. 280 (17): 17163–17171. doi:10.1074/jbc.M501375200. PMC 3092429. PMID 15734731.
• Tripathi MK, Misra S, Chaudhuri G (April 2005). "Negative regulation of the expressions of cytokeratins 8 and 19 by SLUG repressor protein in human breast cells". Biochemical and Biophysical Research Communications. 329 (2): 508–515. doi:10.1016/j.bbrc.2005.02.006. PMC 3086003. PMID 15737616.
• Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, et al. (September 2005). "The transcriptional repressor Snail promotes mammary tumor recurrence". Cancer Cell. 8 (3): 197–209. doi:10.1016/j.ccr.2005.07.009. PMID 16169465.
• Chen M, Chen LM, Chai KX (June 2006). "Androgen regulation of prostasin gene expression is mediated by sterol-regulatory element-binding proteins and SLUG". The Prostate. 66 (9): 911–920. doi:10.1002/pros.20325. PMID 16541421. S2CID 23036264.
• Turner FE, Broad S, Khanim FL, Jeanes A, Talma S, Hughes S, et al. (July 2006). "Slug regulates integrin expression and cell proliferation in human epidermal keratinocytes". The Journal of Biological Chemistry. 281 (30): 21321–21331. doi:10.1074/jbc.M509731200. PMID 16707493.