KLF4 and PBX1 Directly Regulate <i>NANOG</i> Expression in Human Embryonic Stem Cells

Chan, Ken Kwok‐Keung; Zhang, Jingyao; Chia, Na‐Yu; Chan, Yun‐Shen; Sim, Hui Shan; Tan, Ker Sin; Oh, Steve Kah‐Weng; Ng, Huck‐Hui; Choo, Andre

doi:10.1002/stem.143

Cited by 132 publications

(105 citation statements)

References 67 publications

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“…35 The ability of NANOG to promote stem cell self-renewal and proliferation and to generate induced pluripotent stem cells has been well established. 17,18,20,[35][36][37] In this study, we have identified a novel role of NANOG in regulating FLK1 expression and angiogenic activity of ECs.Here, we show that NANOG is expressed in low levels in ECs and in a subset of tumor cell lines. Although the expression of NANOG is thought to be reduced in differentiated cells and tissues, our data show that NANOG is in fact present in mature ECs.…”

mentioning

confidence: 89%

NANOG induction of fetal liver kinase-1 (FLK1) transcription regulates endothelial cell proliferation and angiogenesis

Kohler

Cowan

Chatterjee

et al. 2011

Blood

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NANOG is a master transcription factor associated with the maintenance of stem cell pluripotency. Here, we demonstrate that transcription factor NANOG is expressed in cultured endothelial cells (ECs) and in a subset of tumor cell lines. Importantly, we provide evidence that WNT3A stimulation of ECs induces the transcription of NANOG which mediates the expression of vascular endothelial growth factor receptor-2, also known as fetal liver kinase-1 (FLK1). We defined ATTA as a minimal binding site for NANOG. Accordingly, a luciferase reporter assay showed that NANOG binds to and activates 4 ATTA binding sites identified in the FLK1 promoter after WNT3A stimulation. Consistent with this data, we found that, under basal conditions and in response to WNT3A stimulation, NANOG binding to these ATTA sequences markedly induced the expression of FLK1. Thus, our data indicate an essential role in angiogenesis for NANOG binding to these 4 ATTA sites. Surprisingly, NANOG depletion not only decreased FLK1 expression but also reduced cell proliferation and angiogenesis. These findings show the necessary and sufficient role of NANOG in inducing the transcription of IntroductionAngiogenesis, the sprouting of new capillaries from preexisting blood vessels, is not only required for embryonic development and wound healing but also contributes to pathologic processes, including atherosclerosis, diabetic retinopathy, and tumor progression. 1,2 In this regard, the activation of Wnt (Wingless) signaling in endothelial cells (ECs) has been shown to induce transcriptional events to regulate angiogenesis [3][4][5] ; however, the underlying mechanisms of these processes are not entirely clear. Beyond binding to the cytoplasmic domain of vascular endothelial-or E-cadherin, ␤-catenin plays a key role in the transduction of Wnt signals by serving as a coactivator for the transcription factor T-cell factor/ lymphocyte enhancer binding factor (TCF/LEF-1). 6,7 The ligation of Wnt to the Frizzled receptor induces the inhibition of glycogen synthase kinase-3␤ that results in decreased phosphorylation of ␤-catenin, thereby reduced proteolysis and degradation. [5][6][7] Stabilized ␤-catenin translocates into the nucleus to associate with transcription factors of the TCF/LEF-1 family that can transactivate genes containing TCF/LEF-1 binding sequences. [5][6][7] Recent gene expression profiling has identified a role for Wnt signaling in EC commitment 8 and in control of vasculo-angiogenic aspects of embryonic development. [9][10][11][12][13][14][15] NANOG is a divergent homeobox transcription factor expressed in germ cells and pluripotent stem cells that is critical for morphogenesis and embryonic development. [16][17][18][19] Mouse embryos lacking nanog die between days embryonic (E) 3.5 and E5.5, before any vasculature has developed. 20,21 Nanog overexpression renders mouse embryonic stem (ES) cells independent of leukemia inhibitory factor/signal transducer and activator of transcription-3 stimulation for self-renewal. [17][18][19] Analyses of the ...

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confidence: 89%

NANOG induction of fetal liver kinase-1 (FLK1) transcription regulates endothelial cell proliferation and angiogenesis

Kohler

Cowan

Chatterjee

et al. 2011

Blood

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“…5E). To determine whether forced expression of TRIM6 renders leukemia inhibitory factor (LIF) redundant in ES cells, as in the case of NANOG and KLF4 overexpression (Chan et al, 2009;Darr et al, 2006), we observed E14 cells stably expressing TRIM6 and mock cells without LIF. Although overexpression of TRIM6 in E14 cells caused high expression of NANOG, forced expression of TRIM6 could not maintain the undifferentiation of ES cells without LIF (Fig.…”

Section: Trim6 Regulates the Pluripotency Of Es Cells 1547mentioning

confidence: 99%

TRIM6 interacts with c-Myc and maintains pluripotency of mouse embryonal stem cells

Satô

Okumura

Ariga

et al. 2012

Journal of Cell Science

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SummaryThe proto-oncogene product Myc is a master regulator of cell proliferation through its specific binding to the E-box motif in genomic DNA. It has been reported that Myc has an important role in the proliferation and maintenance of the pluripotency of embryonic stem (ES) cells and that the transcriptional activity of Myc is regulated by several post-translational modifications, including ubiquitination. In this study, we showed that tripartite motif containing 6 (TRIM6), one of the TRIM family ubiquitin ligases, was selectively expressed in ES cells and interacted with Myc followed by attenuation of the transcriptional activity of Myc. Knockdown of TRIM6 in ES cells enhanced the transcriptional activity of Myc and repressed expression of NANOG, resulting in the promotion of ES cell differentiation. These findings indicate that TRIM6 regulates the transcriptional activity of Myc during the maintenance of ES cell pluripotency, suggesting that TRIM6 functions as a novel regulator for Myc-mediated transcription in ES cells.

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“…It was interesting to observe that there was EpICD binding to OCT-4 (distal upstream region) (52), NANOG (upstream region) (53)(54)(55), SOX2 (downstream region) (52), and KLF4 (upstream region) promoters as well, possibly suggesting that that EpCAM modulates ES phenotype through promoting the expression of these downstream targets (Fig. 7C).…”

Section: Suz12 and Jmjd3 Are Required For Bidirectional Regulation Ofmentioning

confidence: 99%

Epithelial Cell Adhesion Molecule Regulation Is Associated with the Maintenance of the Undifferentiated Phenotype of Human Embryonic Stem Cells

Liao

et al. 2010

Journal of Biological Chemistry

113

125

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Human embryonic stem cells (hESCs) are unique pluripotent cells capable of self-renewal and differentiation into all three germ layers. To date, more cell surface markers capable of reliably identifying hESCs are needed. The epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein expressed in several progenitor cell populations and cancers. It has been used to enrich cells with tumor-initiating activity in xenograft transplantation studies. Here, we comprehensively profile the expression of EpCAM by immunofluorescence microscopy, Western blotting, and flow cytometry using an anti-EpCAM monoclonal antibody (mAb) OC98-1. We found EpCAM to be highly and selectively expressed by undifferentiated rather than differentiated hESCs. The protein and transcript level of EpCAM rapidly diminished as soon as hESC had differentiated. This silencing was closely and exclusively associated with the radical transformation of histone modification at the EpCAM promoter. Moreover, we demonstrated that the dynamic pattern of lysine 27 trimethylation of histone 3 was conferred by the interplay of SUZ12 and JMJD3, both of which were involved in maintaining hESC pluripotency. In addition, we used chromatin immunoprecipitation analysis to elucidate the direct regulation by EpCAM of several reprogramming genes, including c-MYC, OCT-4, NANOG, SOX2, and KLF4, to help maintain the undifferentiation of hESCs. Collectively, our results suggest that EpCAM might be used as a surface marker for hESC. The expression of EpCAM may be regulated by epigenetic mechanisms, and it is strongly associated with the maintenance of the undifferentiated state of hESCs.

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KLF4 and PBX1 Directly Regulate NANOG Expression in Human Embryonic Stem Cells

Cited by 132 publications

References 67 publications

NANOG induction of fetal liver kinase-1 (FLK1) transcription regulates endothelial cell proliferation and angiogenesis

NANOG induction of fetal liver kinase-1 (FLK1) transcription regulates endothelial cell proliferation and angiogenesis

TRIM6 interacts with c-Myc and maintains pluripotency of mouse embryonal stem cells

Epithelial Cell Adhesion Molecule Regulation Is Associated with the Maintenance of the Undifferentiated Phenotype of Human Embryonic Stem Cells

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