Id1 Maintains Embryonic Stem Cell Self-Renewal by Up-Regulation of Nanog and Repression of Brachyury Expression

Romero-Lanman, Elizabeth E.; Pavlović, Svetlana; Amlani, Bhishma; Chin, Yvette; Benezra, Robert

doi:10.1089/scd.2011.0428

Cited by 59 publications

(60 citation statements)

References 41 publications

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“…In mESCs, SB treatment, along with suppression of SMAD2, increases the level of Id (Id1 and Id3) genes [34]. Id1 maintains the self-renewal of mESCs by upregulation of Nanog [35]. Similar mechanisms might be controlling the increased Nanog expression in embryos treated with SB.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Transforming Growth Factor β Signaling Promotes Epiblast Formation in Mouse Embryos

Ghimire

Heindryckx

Jeught

et al. 2015

Stem Cells and Development

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Early lineage segregation in preimplantation embryos and maintenance of pluripotency in embryonic stem cells (ESCs) are both regulated by specific signaling pathways. Small molecules have been shown to modulate these signaling pathways. We examined the influence of several small molecules and growth factors on secondlineage segregation of the inner cell mass toward hypoblast and epiblast lineage during mouse embryonic preimplantation development. We found that the second-lineage segregation is influenced by activation or inhibition of the transforming growth factor (TGF)b pathway. Inhibition of the TGFb pathway from the twocell, four-cell, and morula stages onward up to the blastocyst stage significantly increased the epiblast cell proliferation. The epiblast formed in the embryos in which TGFb signaling was inhibited was fully functional as demonstrated by the potential of these epiblast cells to give rise to pluripotent ESCs. Conversely, activating the TGFb pathway reduced epiblast formation. Inhibition of the glycogen synthase kinase (GSK)3 pathway and activation of bone morphogenetic protein 4 signaling reduced the formation of both epiblast and hypoblast cells. Activation of the protein kinase A pathway and of the Janus kinase/signal transducer and activator of transcription 3 pathway did not influence the second-lineage segregation in mouse embryos. The simultaneous inhibition of three pathways-TGFb, GSK3b, and the fibroblast growth factor (FGF)/extracellular signalregulated kinases (Erk)-significantly enhanced the proliferation of epiblast cells than that caused by inhibition of either TGFb pathway alone or by combined inhibition of the GSK3b and FGF/Erk pathways only.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Transforming Growth Factor β Signaling Promotes Epiblast Formation in Mouse Embryos

Ghimire

Heindryckx

Jeught

et al. 2015

Stem Cells and Development

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“…5A) (18,(23)(24)(25). Among these genes, E2F2 RNAi consistently decreased the levels of helixloop-helix gene inhibitor of differentiation 1 (ID1) (Fig.…”

Section: -L)mentioning

confidence: 94%

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Gujar

Mao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

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Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD + ). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD + synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD + levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD + -dependent network. Accordingly, we demonstrate E2F2 is required for GSC selfrenewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix-loop-helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD + metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.T he prognosis for glioblastoma, the most common malignant intrinsic brain tumor in adults, remains poor despite aggressive multidisciplinary therapy, including maximal safe surgical resection, radiation therapy, and temozolomide (1, 2). The failure of these interventions to generate a durable response stems in part from inadequate understanding of the metabolic and molecular mechanisms underlying malignant behavior and therapeutic resistance (3, 4). Nicotinamide adenine dinucleotide (NAD + ) has a well-known role in cellular metabolism and is an important cofactor for signaling pathways that regulate aging, inflammation, diabetes mellitus, axonal injury, and cancer (5, 6). Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD + synthesis, produces NAD + precursor nicotinamide mononucleotide (NMN) to drive NAD + -dependent processes. Interestingly, NAMPT expression is extremely low in the mammalian brain compared with other organs (7,8). However, NAMPT is highly expressed in several cancers, and features of cancer cells, including proliferation, invasion, and tumor growth, exhibit a dependence on NAD + (9-11). In noncancer cells, NAD + plays a critical role in transcriptional control, providing a metabolic basis for epigenetic reprogramming (12-16). Enzymes using NAD + as a cofactor, including the sirtuins and poly-ADP ribosyl transferases, regulate transcription factor activity and chromatin structure (13-15). Additionally, NAD + can control transcription by altering DNA methylation in neurons (12). However, in glioblastoma, little is known about NAD + -dependent transcriptional events and whether these even...

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“…We asked whether inhibitor of differentiation (ID) genes regulated by BMP-SMAD signaling had a role during iPSC generation. ID genes are direct targets of BMP-SMAD signaling in various biological contexts (27)(28)(29)(30), which maintain the pluripotency of mESCs (6,31) and the stem cell identity of several somatic stem cells (32,33). FOP-HDF alleviated the decrease of ID gene expression during iPSC generation (SI Text and Fig.…”

Section: Inhibitor Of Differentiation Genes Regulated By Bmp-smad Sigmentioning

confidence: 99%

BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence

Hayashi

Hsiao

Sami

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Fibrodysplasia ossificans progressiva (FOP) patients carry a missense mutation in ACVR1 [617G > A (R206H)] that leads to hyperactivation of BMP-SMAD signaling. Contrary to a previous study, here we show that FOP fibroblasts showed an increased efficiency of induced pluripotent stem cell (iPSC) generation. This positive effect was attenuated by inhibitors of BMP-SMAD signaling (Dorsomorphin or LDN1931890) or transducing inhibitory SMADs (SMAD6 or SMAD7). In normal fibroblasts, the efficiency of iPSC generation was enhanced by transducing mutant ACVR1 (617G > A) or SMAD1 or adding BMP4 protein at early times during the reprogramming. In contrast, adding BMP4 at later times decreased iPSC generation. ID genes, transcriptional targets of BMP-SMAD signaling, were critical for iPSC generation. The BMP-SMAD-ID signaling axis suppressed p16/INK4A-mediated cell senescence, a major barrier to reprogramming. These results using patient cells carrying the ACVR1 R206H mutation reveal how cellular signaling and gene expression change during the reprogramming processes.reprogramming | pluripotency | BMP | senescence | FOP R eprogramming somatic cells into pluripotent stem cells is an exciting paradigm in biology and has critical implications for transplantation medicine and disease modeling. We developed a method to generate induced pluripotent stem cells (iPSCs) by transducing defined factors, such as OCT4, SOX2, KLF4, and C-MYC (OSKM), into somatic cells (1, 2). These transcription factors regulate the expression of genes important for self-renewal and pluripotency. However, only a small proportion of cells become iPSCs after the introducing these defined factors (3), and this is a major roadblock toward applying this technology for biomedicine. Cytokine-and chemical-induced cell signaling affect the efficiency of iPSC generation (4, 5), but the precise effects and mechanisms in reprogramming are unclear.The BMP-SMAD signal has important roles in the induction and maintenance of pluripotency. BMP promotes the self-renewal of mouse embryonic stem cells (mESCs) (6, 7). In addition, BMP-SMAD signaling facilitates mouse iPSC (miPSC) generation (8). Thus, BMP signaling has positive effects on both the induction and self-renewal of mouse pluripotent stem cells. In contrast, BMPs inhibit self-renewal of human PSCs (9-13). Recently, Hamasaki et al. (15) tried to generate human iPSCs (hiPSCs) from the human dermal fibroblasts (HDFs) of patients with fibrodysplasia ossificans progressiva (FOP; Online Mendelian Inheritance in Man no. 135100) who carried a missense mutation in ACVR1 (617G > A) that leads to hyperactivation of the BMP-SMAD signaling pathway (14), with little success; they obtained many differentiated colonies, but only a few undifferentiated ESC-like colonies. These results indicated that BMP-SMAD signaling negatively affects hiPSC generation as well as their self-renewal.In this study, we independently generated hiPSCs from FOP patients. Although our primary motivation was to establish in vitro disease models of FOP (1...

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Id1 Maintains Embryonic Stem Cell Self-Renewal by Up-Regulation of Nanog and Repression of Brachyury Expression

Cited by 59 publications

References 41 publications

Inhibition of Transforming Growth Factor β Signaling Promotes Epiblast Formation in Mouse Embryos

Inhibition of Transforming Growth Factor β Signaling Promotes Epiblast Formation in Mouse Embryos

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence

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Id1 Maintains Embryonic Stem Cell Self-Renewal by Up-Regulation of Nanog and Repression of Brachyury Expression

Cited by 59 publications

References 41 publications

Inhibition of Transforming Growth Factor β Signaling Promotes Epiblast Formation in Mouse Embryos

Inhibition of Transforming Growth Factor β Signaling Promotes Epiblast Formation in Mouse Embryos

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence

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An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma