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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    • "Among these, we found factors implicated in trophoblast function, such as the transcriptional regulators Bptf (Goller et al. 2008) and Grhl2 (Walentin et al. 2015); Sall4, a TF better known for its role in ESC pluripotency (Zhang et al. 2006; Yang et al. 2008); and components of epigenetic-repressive and nucleosome remodeling complexes (Suz12, Sin3a, and Smca5) (Fig. 2A). Interestingly, we also identified several members of the Integrator complex, thus supporting a previous study suggesting that this complex may form a key part of the basal transcriptional machinery in TSCs (Latos et al. 2015). "
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    ABSTRACT: Elf5 is a transcription factor with pivotal roles in the trophoblast compartment, where it reinforces a trophoblast stem cell (TSC)-specific transcriptional circuit. However, Elf5 is also present in differentiating trophoblast cells that have ceased to express other TSC genes such as Cdx2 and Eomes. In the present study, we aimed to elucidate the context-dependent role of Elf5 at the interface between TSC self-renewal and the onset of differentiation. We demonstrate that precise levels of Elf5 are critical for normal expansion of the TSC compartment and embryonic survival, as Elf5 overexpression triggers precocious trophoblast differentiation. Through integration of protein interactome, transcriptome, and genome-wide chromatin immunoprecipitation data, we reveal that this abundance-dependent function is mediated through a shift in preferred Elf5-binding partners; in TSCs, Elf5 interaction with Eomes recruits Tfap2c to triply occupied sites at TSC-specific genes, driving their expression. In contrast, the Elf5 and Tfap2c interaction becomes predominant as their protein levels increase. This triggers binding to double-and single-occupancy sites that harbor the cognate Tfap2c motif, causing activation of the associated differentiation-promoting genes. These data place Elf5 at the center of a stoichiometry-sensitive transcriptional network, where it acts as a molecular switch governing the balance between TSC proliferation and differentiation.
    Genes & development 11/2015; DOI:10.1101/gad.268821.115 · 10.80 Impact Factor
    • "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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