Function of the Zinc-Finger Transcription Factor SNAI2 in Cancer and Development
Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain. Annual Review of Genetics
(Impact Factor: 15.72).
02/2007; 41(1):41-61. DOI: 10.1146/annurev.genet.41.110306.130146
Elucidation of the molecular mechanisms that underlie disease development is still a tremendous challenge for basic science, and a prerequisite to the development of new and disease-specific targeted therapies. This review focuses on the function of SNAI2, a member of the Snail family of zinc-finger transcription factors, and discusses its possible role in disease development. SNAI2 has been implicated in diseases of melanocyte development and cancer in humans. Many malignancies arise from a rare population of cells that alone have the ability to self-renew and sustain the tumor (i.e., cancer stem cells). SNAI2 controls key aspects of stem cell function in mouse and human, suggesting that similar mechanisms control normal development and cancer stem cell properties. These insights are expected to contribute significantly to the genetics of cancer and to the development of both cancer therapy and new methods for assessing treatment efficacy.
Available from: Nicolo Riggi
- "Several of these activated targets have established roles as oncogenes in other cellular contexts. In contrast, genes directly repressed by EWS-FLI1 include the known tumor suppressors ERRFI1 (Duncan et al., 2010), CABLES1 (Arnason et al., 2013), IER3 (Sebens Mü erkö ster et al., 2008), and TGFBI (Wang et al., 2012) as well as mesenchymal lineage factors such as SNAI2 (Cobaleda et al., 2007), TRPS1 (Zhang et al., 2012), and CD73 (Chamberlain et al., 2007) (Tables S3 and S4). "
[Show abstract] [Hide abstract]
ABSTRACT: The aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation.
Copyright © 2014 Elsevier Inc. All rights reserved.
Available from: Richard M Gronostajski
- "Because Snai2, Meis2 and Nr2f1 are over-expressed in the Nfib-KO, it is possible that some genes in our NFIB-activated set are repressed by these genes instead of being directly activated by NFIB. Repressor activity has been documented for each of these three factors
[22-24]. For example Snai2, which represses transcription via the recruitment of histone deacetylases to target gene promoters
, is known for its antiapoptotic activity and plays a role in epithelial-mesenchymal transition. "
[Show abstract] [Hide abstract]
ABSTRACT: Lung maturation is a late fetal developmental event in both mice and humans. Because of this, lung immaturity is a serious problem in premature infants. Disruption of genes for either the glucocorticoid receptor (Nr3c1) or the NFIB transcription factors results in perinatal lethality due to lung immaturity. In both knockouts, the phenotype includes excess cell proliferation, failure of saccularization and reduced expression of markers of epithelial differentiation. This similarity suggests that the two genes may co-regulate a specific set of genes essential for lung maturation.
We analyzed the roles of these two transcription factors in regulating transcription using ChIP-seq data for NFIB, and RNA expression data and motif analysis for both. Our new ChIP-seq data for NFIB in lung at E16.5 shows that NFIB binds to a NFI motif. This motif is over-represented in the promoters of genes that are under-expressed in Nfib-KO mice at E18.5, suggesting an activator role for NFIB. Using available microarray data from Nr3c1-KO mice, we further identified 52 genes that are under-expressed in both Nfib and Nr3c1 knockouts, an overlap which is 13.1 times larger than what would be expected by chance. Finally, we looked for enrichment of 738 recently published transcription factor motifs in the promoters of these putative target genes and found that the NFIB and glucocorticoid receptor motifs were among the most enriched, suggesting that a subset of these genes may be directly activated by Nfib and Nr3c1.
Our data provide the first evidence for Nfib and Nr3c1 co-regulating genes related to lung maturation. They also establish that the in vivo DNA-binding affinity NFIB is the same as previously seen in vitro, and highly similar to that of the other NFI-family members NFIA, NFIC and NFIX.
Available from: Peter D Pioli
- "All three Snail members have been shown to negatively regulate muscle differentiation by competing for E-box binding with other myogenic regulatory factors (MRFs) [5,10]. Additionally the members of the Snail family have been linked to epithelial-mesenchymal transition, the migration of neural crest cells and generation of neural tubes, the regulation of E-cadherin which is linked to the progression of cancer metastasis, and controlling the response to apoptosis initiators (for reviews, see 11,12). For example, Snai2 deficient animals are more sensitive to total body γ irradiation than WT , and Snai2 deficient hematopoietic progenitor cells demonstrate enhanced levels of apoptosis following radiation-induced DNA damage than WT cells [13,14]. "
[Show abstract] [Hide abstract]
ABSTRACT: The Snail family of transcriptional regulators consists of three highly conserved members. These proteins regulate (repress) transcription via the recruitment of histone deacetylases to target gene promoters that possess the appropriate E-box binding sequences. Murine Snai1 is required for mouse development while Snai2 deficient animals survive with some anomalies. Less is known about the third member of the family, Snai3. To investigate the function of Snai3, we generated a conditional knockin mouse. Utilizing Cre-mediated deletion to facilitate the ablation of Snai3 in T cells or the entire animal, we found little to no effect of the loss of Snai3 in the entire animal or in T cell lineages. This finding provided the hypothesis that absence of Snai3 was mitigated, in part, by the presence of Snai2. To test this hypothesis we created Snai2/Snai3 double deficient mice. The developmental consequences of lacking both of these proteins was manifested in stunted growth, a paucity of offspring including a dramatic deficiency of female mice, and impaired immune cell development within the lymphoid lineages.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.