Alternative titles; symbols
HGNC Approved Gene Symbol: NANOG
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:7,789,402-7,799,146 (from NCBI)
Embryonic stem (ES) cells derived from the inner cell mass (ICM) of blastocysts grow infinitely while maintaining pluripotency. Lif (159540) can maintain self-renewal of mouse ES cells through activation of Stat3 (102582), but is dispensable for maintenance of ICM and human ES cells. In search of a critical factor(s) that underlies pluripotency in both ICM and ES cells, Mitsui et al. (2003) performed in silico differential display and identified several genes specifically expressed in mouse ES cells and preimplantation embryos. One of them, encoding a homeoprotein the authors designated Nanog (from 'Tir Na Nog,' the mythologic Celtic land of the ever-young), was capable of maintaining ES cell self-renewal independently of Lif/Stat3. The mouse Nanog cDNA contains an open reading frame encoding a 305-amino acid polypeptide and has a long 3-prime untranslated region containing a B2 repetitive element. The predicted Nanog protein contains a homeobox domain that is most similar to those of the Nk2 gene family (see 606727). The human Nanog protein (FLJ12581) shares 52% overall amino acid identity with the mouse protein and 85% identity in the homeodomain. Both human and mouse Nanog contain trp-rich repeats, in which trp-x-x-x is repeated 8 and 10 times, respectively. Human Nanog contains an Alu repetitive element in the 3-prime untranslated region. EST database searching identified clones corresponding to human Nanog in libraries from NT2 human teratocarcinoma cells, germ cell and testis tumors, marrow, and other tumors. No EST clones were detected in libraries from normal somatic tissues.
Independently, Chambers et al. (2003) applied expression cloning in mouse ES cells to isolate a self-renewal determinant and obtained a cDNA encoding Nanog. By searching sequence databases, they identified human and rat orthologs of Nanog. The human NANOG protein contains 305 amino acids.
Clark et al. (2004) obtained a full-length cDNA encoding NANOG by PCR of human testis and embryonic stem cell cDNA libraries. Northern blot analysis of human tissues detected weak expression of a 2.2-kb transcript only in adult testis. RT-PCR detected NANOG expression in adult testis and adult and fetal ovary, but not in testis from men with Sertoli cell-only syndrome (see 400042). Real-time PCR detected much higher NANOG expression in seminomas compared with normal testis. NANOG was expressed by undifferentiated cultured human embryonic stem cells, and expression decreased as differentiation progressed.
Hart et al. (2004) identified 3 splice variants of mouse Nanog. The longest variant encodes a 305-amino acid protein, and both shorter variants encode a 279-amino acid protein. RT-PCR detected Nanog expression in undifferentiated mouse ES cells and embryonal carcinoma cells. In preimplantation embryo, expression was detected in morula and blastocysts. Expression was present after implantation, but it was downregulated after embryonic day 8.5. Low levels of Nanog were detected in many adult mouse tissues. In situ hybridization showed Nanog confined to the inner cell mass in mouse blastocysts. Expression was downregulated as epiblast cells entered the primitive streak and underwent epithelial to mesenchymal transition. After the late-bud stage, expression of Nanog waned, and it was not detectable by day 8. In developing gonads, Nanog expression was detected at embryonic day 11.5.
Mitsui et al. (2003) showed that mouse Nanog-deficient ICM failed to generate epiblast and only produced parietal endoderm-like cells. Mouse Nanog-deficient ES cells lost pluripotency and differentiated into extraembryonic endoderm lineage. These data demonstrated that Nanog is a critical factor underlying pluripotency in both ICM and ES cells.
Chambers et al. (2003) determined that Nanog directs propagation of undifferentiated ES cells. Nanog mRNA was present in pluripotent mouse and human cell lines and was absent from differentiated cells. In preimplantation embryos, Nanog was restricted to founder cells from which ES cells could be derived. Endogenous Nanog was found to act in parallel with cytokine stimulation of Stat3 to drive ES cell self-renewal. Elevated Nanog expression from transgene constructs was sufficient for clonal expansion of ES cells, bypassing Stat3 and maintaining Oct4 (164177) levels. Cytokine dependence, multilineage differentiation, and embryo colonization capacity were fully restored upon transgene excision. These findings established a central role for Nanog in the transcription factor hierarchy that defines ES cell identity.
Silva et al. (2006) reported that in fusions between ES cells and neural stem (NS) cells, increased levels of Nanog stimulated pluripotent gene activation from the somatic cell genome and enabled an up to 200-fold increase in the recovery of hybrid colonies, all of which showed ES cell characteristics. Nanog also improved hybrid yield when thymocytes or fibroblasts were fused to ES cells; however, fewer colonies were obtained than from ES x NS cell fusions, consistent with a hierarchical susceptibility to reprogramming among somatic cell types. Notably, for NS x ES cell fusions elevated Nanog enabled primary hybrids to develop into ES cell colonies with identical frequency to homotypic ES x ES fusion products. This meant that in hybrids, increased Nanog was sufficient for the NS cell epigenome to be reset completely to a state of pluripotency. Silva et al. (2006) concluded that Nanog can orchestrate ES cell machinery to instate pluripotency with an efficiency of up to 100% depending on the differentiation status of the somatic cell.
Wang et al. (2006) explored the protein network in which Nanog operates in mouse ES cells. Using affinity purification of Nanog under native conditions followed by mass spectrometry, Wang et al. (2006) identified physically associated proteins. In an iterative fashion they also identified partners of several Nanog-associated proteins (including Oct4), validated the functional relevance of selected newly identified components, and constructed a protein interaction network. The network is highly enriched for nuclear factors that are individually critical for maintenance of the ES cell state and coregulated on differentiation. The network is linked to multiple corepressor pathways and is composed of numerous proteins whose encoding genes are putative direct transcriptional targets of its members. Wang et al. (2006) concluded that this tight protein network seems to function as a cellular module dedicated to pluripotency. Wang et al. (2006) confirmed interaction of Nanog and Dax1 (300473), Nac1 (610672), Zfp281, and Oct4 in several different assays.
Pereira et al. (2006) showed that Tcf3 (604652) limited the steady-state levels of Nanog mRNA, protein, and promoter activity in self-renewing mouse ES cells. Chromatin immunoprecipitation and promoter reporter assays showed that Tcf3 bound to a promoter regulatory region of the Nanog gene and repressed its transcriptional activity. Absence of Tcf3 delayed differentiation of ES cells in vitro by allowing elevated Nanog levels to persist through 5 days of embryoid body formation. Pereira et al. (2006) concluded that TCF3-mediated control of NANOG expression allows ES cells to balance the creation of lineage-committed and undifferentiated cells.
Induced pluripotent stem (iPS) cells can be generated from mouse fibroblasts by retrovirus-mediated introduction of 4 transcription factors and subsequent selection for Fbx15 (609093) expression (Takahashi and Yamanaka, 2006). These iPS cells, hereafter called Fbx15 iPS cells, are similar to embryonic stem (ES) cells in morphology, proliferation, and teratoma formation; however, they are different with regard to gene expression and DNA methylation patterns, and fail to produce adult chimeras. Okita et al. (2007) showed that selection for Nanog expression results in germline-competent iPS cells with increased ES cell-like gene expression and DNA methylation patterns compared with Fbx15 iPS cells. The 4 transgenes, Oct3/4 (164177), Sox2 (184429), c-Myc (190080), and Klf4 (602253), were strongly silenced in Nanog iPS cells. Okita et al. (2007) obtained adult chimeras from 7 Nanog iPS cell clones, with one clone being transmitted through the germline to the next generation. Approximately 20% of the offspring developed tumors attributable to reactivation of the c-Myc transgene. Okita et al. (2007) concluded that iPS cells competent for germline chimeras can be obtained from fibroblasts, but retroviral introduction of c-Myc should be avoided for clinical application.
Wernig et al. (2007) independently demonstrated that the transcription factors Oct4, Sox2, c-Myc, and Klf4 can induce epigenetic reprogramming of a somatic genome to an embryonic pluripotent state. In contrast to selection for Fbx15 activation (Takahashi and Yamanaka, 2006), fibroblasts that had reactivated the endogenous Oct4 (Oct4-neo) or Nanog (Nanog-neo) loci grew independently of feeder cells, expressed normal Oct4, Nanog and Sox2 RNA and protein levels, were epigenetically identical to ES cells by a number of criteria, and were able to generate viable chimeras, contribute to the germline, and generate viable late-gestation embryos after injection into tetraploid blastocysts. Transduction of the 4 factors generated significantly more drug-resistant cells from Nanog-neo than from Oct4-neo fibroblasts, but a higher fraction of Oct4-selected cells had all the characteristics of pluripotent ES cells, suggesting that Nanog activation is a less stringent criterion for pluripotency than Oct4 activation.
Chambers et al. (2007) reported that Nanog fluctuates in mouse embryonic stem cells. Transient downregulation of Nanog appeared to predispose cells towards differentiation but did not mark commitment. By genetic deletion, the authors showed that, although they are prone to differentiate, embryonic stem cells can self-renew indefinitely in the permanent absence of Nanog. Expanded Nanog-null cells colonized embryonic germ layers and exhibited multilineage differentiation both in fetal and adult chimeras. Although they were also recruited to the germ line, primordial germ cells lacking Nanog failed to mature on reaching the genital ridge. This defect was rescued by repair of the mutant allele. Thus, Chambers et al. (2007) concluded that Nanog is dispensable for expression of somatic pluripotency but is specifically required for formation of germ cells. Nanog therefore acts primarily in construction of inner cell mass and germ cell states rather than in the housekeeping machinery of pluripotency. Chambers et al. (2007) surmised that Nanog stabilizes embryonic stem cells in culture by resisting or reversing alternative gene expression states.
Yu et al. (2007) showed that 4 factors, OCT4 (164177), SOX2 (184429), NANOG, and LIN28 (611043), are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem cells. These induced pluripotent human stem cells have normal karyotypes, express telomerase activity, express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all 3 primary germ layers.
Tay et al. (2008) demonstrated the existence of many naturally occurring miRNA targets in the amino acid coding sequences of the mouse Nanog, Oct4, and Sox2 genes. Some of the mouse targets analyzed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. MiRNA134 (610164), miRNA296 (610945), and miRNA470, upregulated on retinoic acid-induced differentiation of mouse embryonic stem cells, target the coding sequence of each transcription factor in various combinations, leading to transcriptional and morphologic changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolished miRNA activity, prevented the downregulation of the corresponding genes, and delayed the induced phenotype. Tay et al. (2008) concluded that their findings demonstrated the abundance of coding sequence-located miRNA targets, some of which can be species-specific, and supported an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3-prime untranslated region.
Hanna et al. (2009) demonstrated that the reprogramming of somatic cells into iPS cells by Oct4, Sox2, Klf4, and Myc transcription factors is a continuous stochastic process where almost all mouse donor cells eventually give rise to iPS cells on continued growth and transcription factor expression. Additional inhibition of the p53 (191170)/p21 (116899) pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell division rate-independent manner. Quantitative analyses defined distinct cell division rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggested that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.
The generation of iPS cells is asynchronous and slow, the frequency is low (less than 0.1%), and DNA demethylation constitutes a bottleneck. To determine regulatory mechanisms involved in reprogramming, Bhutani et al. (2010) generated interspecies heterokaryons (fused mouse ES cells and human fibroblasts) that induced reprogramming synchronously, frequently, and fast. Bhutani et al. (2010) showed that reprogramming toward pluripotency in single heterokaryons was initiated without cell division or DNA replication, rapidly (1 day) and efficiently (70%). Short interfering RNA-mediated knockdown showed that AID (605257) is required for promoter demethylation and induction of OCT4 and NANOG gene expression. AID protein bound silent methylated OCT4 and NANOG promoters in fibroblasts, but not active demethylated promoters in ES cells. Bhutani et al. (2010) concluded that their data provided the first evidence that mammalian AID is required for active DNA demethylation and initiation of nuclear reprogramming toward pluripotency in human somatic cells.
Using chromatin immunoprecipitation sequencing (ChIP-Seq), Kunarso et al. (2010) showed that genomic regions bound by CTCF (604167) were highly conserved between undifferentiated mouse and human embryonic stem cells. However, very little conservation was found for regions bound by OCT4 and NANOG. Most of the differences in OCT4 and NANOG binding between species appeared to be due to species-specific insertion of transposable elements, such as endogenous ERV1 repeats, that generated unique OCT4- and NANOG-repeat-associated binding sites.
Miyanari and Torres-Padilla (2012) showed that Nanog, but not Oct4, is monoallelically expressed in early preimplantation mouse embryos. Nanog then undergoes a progressive switch to biallelic expression during the transition towards ground-state pluripotency in the naive epiblast of the late blastocyst. Embryonic stem (ES) cells grown in leukemia inhibitory factor (LIF; 159540) and serum express Nanog mainly monoallelically and show asynchronous replication of the Nanog locus, a feature of monoallelically expressed genes, but ES cells activate both alleles when cultured under 2i conditions, which mimic the pluripotent ground state in vitro. Live-cell imaging with reporter ES cells confirmed the allelic expression of Nanog and revealed allelic switching. The allelic expression of Nanog is regulated through the fibroblast growth factor (FGF)-extracellular signal-regulated kinase (ERK) signaling pathway, and it is accompanied by chromatin changes at the proximal promoter but occurs independently of DNA methylation. Nanog-heterozygous blastocysts have fewer inner cell-mass derivatives and delayed primitive endoderm formation, indicating a role for the biallelic expression of Nanog in the timely maturation of the inner cell mass into a fully reprogrammed pluripotent epiblast. Miyanari and Torres-Padilla (2012) suggested that the tight regulation of Nanog dose at the chromosome level is necessary for the acquisition of ground-state pluripotency during development. The authors concluded that their data highlighted an unexpected role for allelic expression in controlling the dose of pluripotency factors in vivo, adding an extra level to the regulation of reprogramming.
Doege et al. (2012) described an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as NANOG and ESRRB (602167). By day 4 after transduction with pluripotency factors OCT4 (164177), SOX2 (184429), KLF4 (602253), and MYC (190080) (together referred to as OSKM), 2 epigenetic modification factors necessary for iPSC generation, namely, PARP1 (173870) and TET2 (612839), were recruited to the NANOG and ESRRB loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: PARP1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas TET2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC. Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts, Doege et al. (2012) concluded that their data, and also studies of TET2-mutant human tumor cells, argued in favor of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, PARP1 and TET2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas PARP1 induction further promotes accessibility to the OCT4 reprogramming factor. Doege et al. (2012) concluded that their findings suggested that PARP1 and TET2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.
Using enhanced purification techniques and a stringent computational algorithm, Costa et al. (2013) identified 27 high-confidence protein interaction partners of Nanog in mouse embryonic stem cells. These consisted of 19 partners of Nanog, including the ten-eleven translocation (TET) family methylcytosine hydroxylase Tet1 (607790). Costa et al. (2013) confirmed physical association of Nanog with Tet1, and demonstrated that Tet1, in synergy with Nanog, enhanced the efficiency of reprogramming. Costa et al. (2013) also found physical association and reprogramming synergy of Tet2 with Nanog, and demonstrated that knockdown of Tet2 abolished the reprogramming synergy of Nanog with a catalytically deficient mutant of Tet1. These results indicated that the physical interaction between Nanog and Tet1/Tet2 proteins facilitates reprogramming in a manner that is dependent on the catalytic activity of Tet1/Tet2. Tet1 and Nanog cooccupy genomic loci of genes associated with both maintenance of pluripotency and lineage commitment in embryonic stem cells, and Tet1 binding is reduced upon Nanog depletion. Coexpression of Nanog and Tet1 increased 5-hydroxymethylcytosine levels at the top-ranked common target loci Esrrb and Oct4, resulting in priming of their expression before reprogramming to naive pluripotency. Costa et al. (2013) proposed that TET1 is recruited by NANOG to enhance the expression of a subset of key reprogramming target genes.
After fertilization, maternal factors direct development and trigger zygotic genome activation (ZGA) at the maternal-to-zygotic transition. In zebrafish, ZGA is required for gastrulation and clearance of maternal mRNAs, which is in part regulated by the conserved microRNA miR430 (homologous to human MIR302A, 614596). Lee et al. (2013) showed that Nanog, Pou5f1 (164177), and SoxB1 regulate zygotic gene activation in zebrafish. Lee et al. (2013) identified several hundred genes directly activated by maternal factors, constituting the first wave of zygotic transcription. Ribosome profiling revealed that Nanog, Sox19B (a member of the SoxB1 family), and Pou5f1 are the most highly translated transcription factors prior to maternal-to-zygotic transition. Combined loss of these factors resulted in developmental arrest before gastrulation and a failure to activate greater than 75% of zygotic genes, including miR430. Lee et al. (2013) concluded that maternal Nanog, Pou5f1, and SoxB1 are required to initiate the zygotic developmental program and induce clearance of the maternal program by activating miR430 expression.
De Wit et al. (2013) combined chromatin conformation capture technologies with chromatin factor binding data to demonstrate that inactive chromatin is unusually disorganized in pluripotent stem cell nuclei. They showed that gene promoters engage in contacts between topologic domains in a largely tissue-independent manner, whereas enhancers have a more tissue-restricted interaction profile. Notably, genomic clusters of pluripotency factor binding sites find each other very efficiently, in a manner that is strictly pluripotent stem cell-specific, dependent on the presence of Oct4 (Pou5f1) and Nanog proteins, and inducible after artificial recruitment of Nanog to a selected chromosomal site. De Wit et al. (2013) concluded that pluripotent stem cells have a unique higher-order genome structure shaped by pluripotency factors, and speculated that this interactome enhances the robustness of the pluripotent state.
Murakami et al. (2016) investigated the role of Nanog in mouse unipotent primordial germ cells in an in vitro model, in which naive pluripotent ES cells cultured in basic fibroblast growth factor (bFGF) and activin A develop as epiblast-like cells (EpiLCs) and gain competence for a PGC-like fate. Consequently, bone morphogenetic protein-4 (BMP4; 112262), or ectopic expression of key germline transcription factors Prdm1 (603423), Prdm14 (611781), and Tfap2c (601602), directly induce PGC-like cells (PGCLCs) in EpiLCs but not in ES cells. Murakami et al. (2016) found that that, unexpectedly, Nanog alone can induce PGCLCs in EpiLCs independently of BMP4, and proposed that after the dissolution of the naive ES-cell pluripotency network during establishment of EpiLCs, the epigenome is reset for cell fate determination. Indeed, Murakami et al. (2016) found genomewide changes in Nanog-binding patterns between ES cells and EpiLCs, indicating epigenetic resetting of regulatory elements. Accordingly, the authors showed that Nanog can bind and activate enhancers of Prdm1 and Prdm14 in EpiLCs in vitro; Blimp1 (encoded by Prdm1) then directly induces Tfap2c. Furthermore, while Sox2 and Nanog promote the pluripotent state in ES cells, they show contrasting roles in EpiLCs, as Sox2 specifically represses PGCLC induction by Nanog. The study of Murakami et al. (2016) demonstrated a broadly applicable mechanistic principle for how cells acquire competence for cell fate determination, resulting in the context-dependent roles of key transcription factors during development.
Hart et al. (2004) determined that the NANOG gene contains 4 exons and spans 7 kb.
Mitsui et al. (2003) determined that the mouse Nanog gene contains 4 exons. Hart et al. (2004) identified 2 additional upstream exons in the mouse Nanog gene that are used in alternatively spliced transcripts.
Mitsui et al. (2003) stated that the human Nanog gene maps to chromosome 12 in a region showing homology of synteny to mouse chromosome 6, where the mouse Nanog gene is located.
By genomic sequence analysis, Clark et al. (2004) mapped the NANOG gene to chromosome 12p13. Hart et al. (2004) identified a duplicate NANOG gene, which they called NANOG2 (NANOGP1), about 100 kb upstream of the NANOG gene. The 2 genes are in a head-to-tail configuration. Hart et al. (2004) also identified NANOG pseudogenes on chromosomes 15q, 7p, 14q, 2q, Xp, and Xq.
Bhutani, N., Brady, J. J., Damian, M., Sacco, A., Corbel, S. Y., Blau, H. M. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463: 1042-1047, 2010. [PubMed: 20027182] [Full Text: https://doi.org/10.1038/nature08752]
Chambers, I., Colby, D., Robertson, M., Nichols, J., Lee, S., Tweedie, S., Smith, A. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113: 643-655, 2003. [PubMed: 12787505] [Full Text: https://doi.org/10.1016/s0092-8674(03)00392-1]
Chambers, I., Silva, J., Colby, D., Nichols, J., Nijmeijer, B., Robertson, M., Vrana, J., Jones, K., Grotewold, L., Smith, A. Nanog safeguards pluripotency and mediates germline development. Nature 450: 1230-1234, 2007. [PubMed: 18097409] [Full Text: https://doi.org/10.1038/nature06403]
Clark, A. T., Rodriguez, R. T., Bodnar, M. S., Abeyta, M. J., Cedars, M. I., Turek, P. J., Firpo, M. T., Pera, R. A. R. Human STELLAR, NANOG, and GDF3 genes are expressed in pluripotent cells and map to chromosome 12p13, a hotspot for teratocarcinoma. Stem Cells 22: 169-179, 2004. [PubMed: 14990856] [Full Text: https://doi.org/10.1634/stemcells.22-2-169]
Costa, Y., Ding, J., Theunissen, T. W., Faiola, F., Hore, T. A., Shliaha, P. V., Fidalgo, M., Saunders, A., Lawrence, M., Dietmann, S., Das, S., Levasseur, D. N., Li, Z., Xu, M., Reik, W., Silva, J. C. R., Wang, J. NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495: 370-374, 2013. [PubMed: 23395962] [Full Text: https://doi.org/10.1038/nature11925]
de Wit, E., Bouwman, B. A. M., Zhu, Y., Klous, P., Splinter, E., Verstegen, M. J. A. M., Krijger, P. H. L., Festuccia, N., Nora, E. P., Welling, M., Heard, E., Geijsen, N., Poot, R. A., Chambers, I., de Laat, W. The pluripotent genome in three dimensions is shaped around pluripotency factors. Nature 501: 227-231, 2013. [PubMed: 23883933] [Full Text: https://doi.org/10.1038/nature12420]
Doege, C. A., Inoue, K., Yamashita, T., Rhee, D. B., Travis, S., Fujita, R., Guarnieri, P., Bhagat, G., Vanti, W. B., Shih, A., Levine, R. L., Nik, S., Chen, E. I., Abeliovich, A. Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 488: 652-655, 2012. [PubMed: 22902501] [Full Text: https://doi.org/10.1038/nature11333]
Hanna, J., Saha, K., Pando, B., van Zon, J., Lengner, C. J., Creyghton, M. P., van Oudenaarden, A., Jaenisch, R. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462: 595-601, 2009. [PubMed: 19898493] [Full Text: https://doi.org/10.1038/nature08592]
Hart, A. H., Hartley, L., Ibrahim, M., Robb, L. Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human. Dev. Dyn. 230: 187-198, 2004. [PubMed: 15108323] [Full Text: https://doi.org/10.1002/dvdy.20034]
Kunarso, G., Chia, N.-Y., Jeyakani, J., Hwang, C., Lu, X., Chan, Y.-S., Ng, H.-H., Bourque, G. Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nature Genet. 42: 631-634, 2010. [PubMed: 20526341] [Full Text: https://doi.org/10.1038/ng.600]
Lee, M. T., Bonneau, A. R., Takacs, C. M., Bazzini, A. A., DiVito, K. R., Fleming, E. S., Giraldez, A. J. Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to-zygotic transition. Nature 503: 360-364, 2013. [PubMed: 24056933] [Full Text: https://doi.org/10.1038/nature12632]
Mitsui, K., Tokuzawa, Y., Itoh, H., Segawa, K., Murakami, M., Takahashi, K., Maruyama, M., Maeda, M., Yamanaka, S. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113: 631-642, 2003. [PubMed: 12787504] [Full Text: https://doi.org/10.1016/s0092-8674(03)00393-3]
Miyanari, Y., Torres-Padilla, M.-E. Control of ground-state pluripotency by allelic regulation of Nanog. Nature 483: 470-473, 2012. [PubMed: 22327294] [Full Text: https://doi.org/10.1038/nature10807]
Murakami, K., Gunesdogan, U., Zylicz, J. J., Tang, W. W. C., Sengupta, R., Kobayashi, T., Kim, S., Butler, R., Dietmann, S., Surani, M. A. NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers. Nature 529: 403-407, 2016. [PubMed: 26751055] [Full Text: https://doi.org/10.1038/nature16480]
Okita, K., Ichisaka, T., Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448: 313-317, 2007. [PubMed: 17554338] [Full Text: https://doi.org/10.1038/nature05934]
Pereira, L., Yi, F., Merrill, B. J. Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal. Molec. Cell. Biol. 26: 7479-7491, 2006. [PubMed: 16894029] [Full Text: https://doi.org/10.1128/MCB.00368-06]
Silva, J., Chambers, I., Pollard, S., Smith, A. Nanog promotes transfer of pluripotency after cell fusion. Nature 441: 997-1001, 2006. [PubMed: 16791199] [Full Text: https://doi.org/10.1038/nature04914]
Takahashi, K., Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-676, 2006. [PubMed: 16904174] [Full Text: https://doi.org/10.1016/j.cell.2006.07.024]
Tay, Y., Zhang, J., Thomson, A. M., Lim, B., Rigoutsos, I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 455: 1124-1128, 2008. Note: Erratum: Nature 458: 538 only, 2009. [PubMed: 18806776] [Full Text: https://doi.org/10.1038/nature07299]
Wang, J., Rao, S., Chu, J., Shen, X., Levasseur, D. N., Theunissen, T. W., Orkin, S. H. A protein interaction network for pluripotency of embryonic stem cells. Nature 444: 364-368, 2006. [PubMed: 17093407] [Full Text: https://doi.org/10.1038/nature05284]
Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., Bernstein, B. E., Jaenisch, R. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448: 318-324, 2007. [PubMed: 17554336] [Full Text: https://doi.org/10.1038/nature05944]
Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., Slukvin, I. I., Thomson, J. A. Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917-1920, 2007. [PubMed: 18029452] [Full Text: https://doi.org/10.1126/science.1151526]