Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in murine-embryonic stem cells

Chai, Li; Fowles, Taylor C.; Alipio, Zaida; Xu, Dan; Fink, Louis M.; Ward, David C.; Ma, Yupo

doi:10.1073/pnas.0809321105

Cited by 182 publications

(186 citation statements)

References 35 publications

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“…Using gene expression profiling approaches, we recently identified the activation of transcription factor Sal-like protein 4transcription 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].…”

Section: Introductionmentioning

confidence: 99%

Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

Nio

Yamashita

Okada

et al. 2015

Journal of Hepatology

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Background & Aims: 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. Methods: 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 CHD4 was evaluated in primary hepatocellular carcinoma cells and in cell lines in vitro and in vivo. Results: CHD4 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 CHD4 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.Conclusions: CHD4 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. Ó

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Section: Introductionmentioning

confidence: 99%

Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

Nio

Yamashita

Okada

et al. 2015

Journal of Hepatology

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“…S2C) followed by mass spectrometry (van den Berg et al 2010) to identify Elf5-binding partners in an unbiased manner. 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).…”

Section: Elf5 Protein Interactomementioning

confidence: 99%

Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks

et al. 2015

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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 abundancedependent 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 differentiationpromoting 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.

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“…Transcriptional regulation is at the heart of the events leading to development, differentiation, and tissue maintenance: not surprisingly, a selected cohort of transcription factors (TFs) are key to ES stemness, by promoting their regulated growth and preventing differentiation. Among these, SOX2, OCT4, KLF4, SALL4, MYC, and NANOG are also involved in the process of reprogramming of differentiated cells to become ES, or ES-like induced pluripotent stem (iPS) cells; genome-wide analysis has established a network of coregulation among these TFs in ESCs [1][2][3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

The Short Isoform of NF‐YA Belongs to the Embryonic Stem Cell Transcription Factor Circuitry

et al. 2012

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Totipotency of embryonic stem cells (ESCs) is controlled at the transcriptional level by a handful of transcription factors (TFs) that promote stemness and prevent differentiation. One of the most enriched DNA elements in promoters and enhancers of genes specifically active in ESCs is the CCAAT box, which is recognized by NF-Y, a trimer with histone-like subunits-NF-YB/NF-YC-and the sequence-specific NF-YA. We show that the levels of the short NF-YA isoform-NF-YAs-is high in mouse ESCs (mESCs) and drops after differentiation; a dominant negative mutant affects expression of important stem cells genes, directly and indirectly. Protein transfections of TAT-NF-YAs stimulate growth and compensate for withdrawal of leukemia inhibitory factor (LIF) in cell cultures. Bioinformatic analysis identifies NF-Y sites as highly enriched in genomic loci of stem TFs in ESCs. Specifically, 30%-50% of NANOG peaks have NF-Y sites and indeed NF-Y-binding is required for NANOG association to DNA. These data indicate that NF-Y belongs to the restricted circle of TFs that govern mESCs, and, specifically, that NF-YAs is the active isoform in these cells.

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Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in murine-embryonic stem cells

Abstract: induced pluripotent stem cells ͉ epigenetic regulation ͉ Oct4 ͉ Nanog ͉ Sox2

Cited by 182 publications

References 35 publications

Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks

The Short Isoform of NF‐YA Belongs to the Embryonic Stem Cell Transcription Factor Circuitry

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