Genome-Wide Analysis Reveals Sall4 to Be a Major Regulator of Pluripotency in Murine-Embryonic Stem Cells

Division of Laboratory Medicine, Nevada Cancer Institute, One Breakthrough Way, Las Vegas, NV 89135, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2009; 105(50):19756-61. DOI: 10.1073/pnas.0809321105
Source: PubMed


Embryonic stem cells have potential utility in regenerative medicine because of their pluripotent characteristics. Sall4, a zinc-finger transcription factor, is expressed very early in embryonic development with Oct4 and Nanog, two well-characterized pluripotency regulators. Sall4 plays an important role in governing the fate of stem cells through transcriptional regulation of both Oct4 and Nanog. By using chromatin immunoprecipitation coupled to microarray hybridization (ChIP-on-chip), we have mapped global gene targets of Sall4 to further investigate regulatory processes in W4 mouse ES cells. A total of 3,223 genes were identified that were bound by the Sall4 protein on duplicate assays with high confidence, and many of these have major functions in developmental and regulatory pathways. Sall4 bound approximately twice as many annotated genes within promoter regions as Nanog and approximately four times as many as Oct4. Immunoprecipitation revealed a heteromeric protein complex(es) between Sall4, Oct4, and Nanog, consistent with binding site co-occupancies. Decreasing Sall4 expression in W4 ES cells decreases the expression levels of Oct4, Sox2, c-Myc, and Klf4, four proteins capable of reprogramming somatic cells to an induced pluripotent state. Further, Sall4 bound many genes that are regulated in part by chromatin-based epigenetic events mediated by polycomb-repressive complexes and bivalent domains. This suggests that Sall4 plays a diverse role in regulating stem cell pluripotency during early embryonic development through integration of transcriptional and epigenetic controls.

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Available from: Li Chai, Oct 10, 2015
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    • "Defeating EpCAM + liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma. J Hepatol (2015), transcription factor which plays a fundamental role in the maintenance of embryonic stem cells, possibly through interaction with octamer-binding transcription factor 4, sex determining region Y-box 2, and Nanog [19] [20] [21] [22] [23] [24]. It has been reported by three independent groups that SALL4 is a biomarker of HCCs with stem-like gene expression signatures and a poor prognosis [18] [25] [26]. "
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    ABSTRACT: Hepatocellular carcinoma is composed of a subset of cells with enhanced tumorigenicity and chemoresistance that are called cancer stem (or stem-like) cells. We explored the role of chromodomain-helicase-DNA-binding protein 4, which is encoded by the CHD4 gene and is known to epigenetically control gene regulation and DNA damage responses in EpCAM(+) liver cancer stem cells. Gene and protein expression profiles were determined by microarray and immunohistochemistry in 245 and 144 hepatocellular carcinoma patients, respectively. The relationship between gene/protein expression and prognosis was examined. The functional role of chromodomain-helicase-DNA-binding protein 4 was evaluated in primary hepatocellular carcinoma cells and in cell lines in vitro and in vivo. Chromodomain helicase DNA-binding protein 4 was abundantly expressed in EpCAM(+) hepatocellular carcinoma with expression of hepatic stem cell markers and poor prognosis in two independent cohorts. In cell lines, CHD4 knockdown increased chemosensitivity and CHD4 overexpression induced epirubicin chemoresistance. To inhibit the functions of chromodomain-helicase-DNA-binding protein 4 that are mediated through histone deacetylase and poly (ADP-ribose) polymerase, we evaluated the effect of the histone deacetylase inhibitor suberohydroxamic acid and the poly (ADP-ribose) polymerase inhibitor AG-014699. Treatment with either suberohydroxamic acid or AG-014699 reduced the number of EpCAM(+) liver cancer stem cells in vitro, and suberohydroxamic acid and AG-014699 in combination successfully inhibited tumor growth in a mouse xenograft model. Chromodomain-helicase-DNA-binding protein 4 plays a pivotal role in chemoresistance and the maintenance of stemness in liver cancer stem cells and is therefore a good target for the eradication of hepatocellular carcinoma. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 06/2015; DOI:10.1016/j.jhep.2015.06.009 · 11.34 Impact Factor
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    • "Chromatin remodeling plays essential roles in stem cell fate decisions. SALL4 may regulate this process by connecting transcriptional regulation and epigenetic regulation in stem cells (Yang et al., 2008). SALL4 can recruit either the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex, epigenetic repressor, or histone methyltransferase complex to specific promoter regions, resulting in histone deacetylation or H3K4 trimethylation, respectively. "
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    ABSTRACT: Human cancer cells resemble stem cells in expression signatures leading them to share some features, most notably, self-renewal. A complex network of transcription factors and signaling molecules are required for continuation of this trait. ZNF797 (SALL4) is a zinc finger transcriptional activator crucial for maintenance of self-renewal in stem cells; however, its expression level has not yet been elucidated in gastric tumor cells. Its expression was analyzed to determine this level and probable clinicopathological consequences. SALL4 expression in fresh tumor and distant tumor-free tissues from 46 colorectal samples was compared by real-time polymerase chain reaction. Greater than a 2-fold increase in SALL4 expression was detected in 89.5% of tumors vs normal related tissues. SALL4 expression was significantly correlated with tumor cell metastasis to lymph nodes, especially in moderately differentiated tumor samples (P < 0.05). Furthermore, higher levels of SALL4 mRNA expression were significantly associated with younger patients with tumor cells in stages I and II (P < 0.05). These results indicate a relationship between SALL4 expression and tumor cell metastasis to lymph nodes and consequent progression of tumors to advanced stages III and IV. Along with the promising evidence of its role in self-renewal in various cancers, SALL4 is introduced as a potentially interesting therapeutic target to reverse a number of aberrations that promote gastric tumor development and maintenance. This result may lead to new approaches for cancer therapy.
    Genetics and molecular research: GMR 10/2014; 13(4):8421-7. DOI:10.4238/2014.October.20.18 · 0.78 Impact Factor
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    • "In addition, SALL4B can regulate its own promoter [20]. In order to test if TAT-SALL4B bears similar functional activities, we constructed OCT4 and SALL4 luciferase promoter reporters into 293 T cells, we found TAT-SALL4B protein could regulate OCT4 and SALL4 promoter activities in a similar pattern to that reported in previous study [19] (Figure 1d). The TAT-SALL4B protein significantly upregulated OCT4 and downregulated SALL4 promoter activities. "
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    ABSTRACT: Hematopoietic stem cells (HSCs) are widely used in transplantation therapy to treat a variety of blood diseases. The success of hematopoietic recovery is of high importance and closely related to the patient's morbidity and mortality after Hematopoietic stem cell transplantation (HSCT). We have previously shown that SALL4 is a potent stimulator for the expansion of human hematopoietic stem/progenitor cells in vitro. In these studies, we demonstrated that systemic administration with TAT-SALL4B resulted in expediting auto-reconstitution and inducing a 30-fold expansion of endogenous HSCs/HPCs in mice exposed to a high dose of irradiation. Most importantly, TAT-SALL4B treatment markedly prevented death in mice receiving lethal irradiation. Our studies also showed that TAT-SALL4B treatment was able to enhance both the short-term and long-term engraftment of human cord blood (CB) cells in NOD/SCID mice and the mechanism was likely related to the in vivo expansion of donor cells in a recipient. This robust expansion was required for the association of SALL4B with DNA methyltransferase complex, an epigenetic regulator critical in maintaining HSC pools and in normal lineage progression. Our results may provide a useful strategy to enhance hematopoietic recovery and reconstitution in cord blood transplantation with a recombinant TAT-SALL4B fusion protein.
    Journal of Hematology & Oncology 11/2013; 6(1):84. DOI:10.1186/1756-8722-6-84 · 4.81 Impact Factor
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