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NANOG metabolically reprograms tumor-initiating stem-like cells in oxidative phosphorylation and fatty acid metabolism

ABSTRACT: Stem cell markers such as NANOG have been implicated in various cancers; however, the functional contribution of NANOG to cancer pathogenesis has remained unclear. In the present study, we show that Toll-like receptor 4 (TLR4) signaling phosphorylates E2F1 to transactivate NANOG. Down-regulation of Nanog significantly reduces tumor development. In the search for the NANOG-dependent mechanisms underlying growth of tumor-initiating stem-like cells (TICs), NANOG ChIP-seq identifies the genes associated with mitochondrial metabolic pathways. Genome wide Identification of Nanog binding partners in tumor initating stem cells

ORGANISM(S): Mus musculus

SUBMITTER: Vasu Punj

PROVIDER: E-GEOD-68237 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism.

Chen Chia-Lin CL Uthaya Kumar Dinesh Babu DB Punj Vasu V Xu Jun J Sher Linda L Tahara Stanley M SM Hess Sonja S Machida Keigo K

Cell metabolism 20151224 1

Stem cell markers, including NANOG, have been implicated in various cancers; however, the functional contribution of NANOG to cancer pathogenesis has remained unclear. Here, we show that NANOG is induced by Toll-like receptor 4 (TLR4) signaling via phosphorylation of E2F1 and that downregulation of Nanog slows down hepatocellular carcinoma (HCC) progression induced by alcohol western diet and hepatitis C virus protein in mice. NANOG ChIP-seq analyses reveal that NANOG regulates the expression of ...[more]

PMID: 26724859

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Alternative routes to induced pluripotent stem cells revealed by reprogramming of neural lineage

Project description:During the reprogramming of mouse embryonic fibroblasts (MEFs) to induced pluripotent stem cells, the activation of pluripotency genes such as Nanog occurs after the mesenchymal to epithelial transition (MET). Here we report that both adult stem cells (neural stem cells- NSCs) and differentiated cells (astrocytes) of the neural lineage can activate Nanog in the absence of cadherin expression during reprogramming. Gene expression analysis revealed that only the Nanog+Ecadherin+ populations expressed stabilization markers and had upregulated several cell cycle genes; and were transgene independent. Inhibition of Dot1L activity, which has previously been shown to increase MET, enhanced both the numbers of Nanog+ and Nanog+E-cadherin+ colonies, suggesting a MET independent pathway for activation of Nanog in NSCs. Expressing Sox2 in MEFs prior to reprogramming does not alter the ratio of Nanog colonies that express E-cadherin obtained. Taken together these results provide a novel pathway for reprogramming taken by cells of the neural lineage. Neural Stem Cells (NSCs) were induced to reprogram by the induction of Oct4, Sox2, c-Myc and Klf4. Reprogramming colonies that expressed either Nanog alone (N+E-) or Nanog and E-cadherin (N+E+) were sorted by flow cytometry and used as input for RNA-sequencing. There are 3 replicates each for the N+E- and N+E+ samples.

2016-02-18 | E-GEOD-76130 | biostudies-arrayexpress

Genome-wide maps of binding sites of Nanog-like and Mxtx2 in blastula stage zebrafish embryos

Project description:Here, using ChIP-Seq, we examined the targets of Nanog-like and Mxtx2 in blastula stage zebrafish embryos. We found that Nanog-like bind to its known targets like Oct4, Sox2, and Nanog-like. Nanog-like also bound to genes involved in extraembryonic lineage differentiation, like gata3 and krt4 for EVL differentiation, and mxtx2 and slc26a1 for YSL differentiation, mesoderm specification like ntl and tbx3, cell movement like wnt11 and cxcr4b, and signaling genes like ndr1, bmp2b, fgf8a and wnt8a. The binding profile suggests that Nanog-like may play a versatile role involving many developmental processes. We found 11.3% of the genes (1751 out of all annotated 15500 zebrafish genes) and 43.6% of the YSL genes (118 out of 271 genes expressed in the YSL) were bound by Mxtx2, suggesting Mxtx2 bound directly to YSL genes to activate their expression Examination of Nanog-like and Mxtx2 binding sites in 3.5hpf and 4.5hpf zebrafish embryos

2011-12-28 | E-GEOD-34683 | biostudies-arrayexpress

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2016-12-19 | PXD003798 | Pride

Activin/Nodal signalling controls divergent transcriptional networks in pluripotent and endoderm progenitors.

Project description:Activin/Nodal signalling is necessary to maintain pluripotency of human Embryonic Stem Cells (hESCs) and to induce their differentiation towards endoderm. However, the mechanisms by which Activin/Nodal signalling achieves these opposite functions remain unclear. To unravel these mechanisms, we examined the transcriptional network controlled in hESCs by Smad2 and Smad3 which represent the direct effectors of Activin/Nodal signalling. These analyses reveal that Smad2/3 participate in the control of the core transcriptional network characterising pluripotency which includes Oct-4, Nanog, FoxD3, Dppa4, Tert, Myc and UTF-1. In addition, similar experiments performed on endoderm cells confirm that a broad part of the transcriptional network directing differentiation is downstream of Smad2/3. Therefore, Activin/Nodal signalling appears to control divergent transcriptional networks in hESCs and in endoderm. Importantly, we observed an overlap between the transcriptional network downstream of Nanog and Smad2/3 in hESCs while functional studies showed that both factors cooperate to control the expression of pluripotency genes. Therefore, the effect of Activin/Nodal signalling on pluripotency and differentiation could be dictated by tissue specific Smad2/3 partners such as Nanog, explaining the mechanisms by which signalling pathways can orchestrate divergent cell fate decisions. Identification of Smad2/3 binding sites in pluripotent hESCs. 5 ChIP-Seq samples including 1 input control sample and 4 ChIP samples (two conditions x two replicates).

2011-11-11 | E-GEOD-19461 | biostudies-arrayexpress

NANOG metabolically reprograms tumor-initiating stem-like cells in oxidative phosphorylation and fatty acid metabolism

Project description:Stem cell markers such as NANOG have been implicated in various cancers; however, the functional contribution of NANOG to cancer pathogenesis has remained unclear. In the present study, we show that Toll-like receptor 4 (TLR4) signaling phosphorylates E2F1 to transactivate NANOG. Down-regulation of Nanog significantly reduces tumor development. In the search for the NANOG-dependent mechanisms underlying growth of tumor-initiating stem-like cells (TICs), NANOG ChIP-seq identifies the genes associated with mitochondrial metabolic pathways.

2016-01-07 | GSE68237 | GEO

Nanog-like Regulates Endoderm Formation through the Mxtx2-Nodal Pathway

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2011-12-28 | E-GEOD-34684 | biostudies-arrayexpress

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2015-11-22 | E-GEOD-72145 | biostudies-arrayexpress

Nanog Independent Reprogramming to iPSCs with Canonical Factors

Project description:It has been suggested that the transcription factor Nanog is essential for the establishment of pluripotency during the derivation of embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. However, successful reprogramming to pluripotency with a growing list of divergent transcription factors, at ever increasing efficiencies, suggests that there may be many distinct routes to a pluripotent state. Here, we have investigated whether Nanog is necessary for reprogramming murine fibroblasts under highly efficient conditions using the canonical reprogramming factors Oct4, Sox2, Klf4 and cMyc. In agreement with prior results, the efficiency of reprogramming Nanog-/- fibroblasts was significantly lower than that of control fibroblasts. However, in contrast to previous findings, we were able to reproducibly generate iPS cells from Nanog-/- fibroblasts that effectively contributed to chimeric mice. Thus while Nanog may be an important mediator of reprogramming it is not required for establishing pluripotency in the mouse, even under standard conditions. In order to further evaluate the equivalency of Nanog null iPSC to nanog null ESCs, we have performed RNAseq on two independent nanog null iPSC lines, as well as Nanog Null ESC, WT ESC and iPSCs as well as MEFs. As a negativve control for reprogramming we have analyzed a partially reprogrammed iPSC line. 2-4 biological replicates each of 7 conditions (WT MEFs, WT ESC, WT iPSC, WT partially reprogrammed iPSC (piPS), Nanog null ESC, Nanog null iPSC clone G2 and Nanog null iPSC clone G5)

2014-01-01 | E-GEOD-53212 | biostudies-arrayexpress

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