Disease relevance of NANOG

• METHODS AND RESULTS: We detected abundant expression of NANOG in CIS and in CIS-derived testicular tumours with marked differences; seminoma and embryonal carcinoma were strongly positive, differentiated somatic elements of teratoma were negative [1].
• Our recent genome-wide gene expression profiling study of the precursor of testicular germ cell tumours, carcinoma in situ testis (CIS), showed close similarity between ESC and CIS, including high NANOG expression [1].
• We provide evidence for the fetal origin of testicular cancer as we detected strong expression of NANOG in fetal gonocytes up to gestational week 20, with subsequent down-regulation occurring earlier than for OCT-4 [1].
• Human STELLAR, NANOG, and GDF3 genes are expressed in pluripotent cells and map to chromosome 12p13, a hotspot for teratocarcinoma [2].
• In addition, the NANOG protein was expressed in the majority of seminoma cells [3].

High impact information on NANOG

• We found, surprisingly, that OCT4, SOX2, and NANOG co-occupy a substantial portion of their target genes [4].
• Nanog: a new recruit to the embryonic stem cell orchestra [5].
• Nanog, a homeobox transcription factor, plays a crucial role in the second embryonic cell fate specification following formation of the blastocyst [5].
• Nanog mRNA is present in pluripotent mouse and human cell lines, and absent from differentiated cells [6].
• Elevated Nanog expression from transgene constructs is sufficient for clonal expansion of ES cells, bypassing Stat3 and maintaining Oct4 levels [6].

Biological context of NANOG

• Here we describe the location, genomic organization, and relative ages of all human NANOG pseudogenes, comprising ten processed pseudogenes and one tandem duplicate [7].
• Indeed, PD98059 prevented Nanog repression induced by ES cell aggregation as well [8].
• Furthermore, transfection of a constitutive active Mek mutant into ES cells induced Nanog repression and primitive endoderm differentiation [8].
• Chromatin immunoprecipitation and promoter reporter assays showed that Tcf3 bound to a promoter regulatory region of the Nanog gene and repressed its transcriptional activity in ESC through a Groucho interaction domain-dependent process [9].
• These data indicate that the Grb2/Mek pathway primarily mediates Nanog gene repression upon ES cell differentiation into primitive endoderm [8].

Anatomical context of NANOG

• These results provide new insights into the transcriptional regulation of stem cells and reveal how OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal [4].
• To examine the function of NANOG in primate ES cells, we generated transgenic monkey ES cell lines expressing three- to seven-fold higher levels of NANOG protein compared to wild-type ES cells [10].
• In the present study we analysed the protein expression of NANOG during normal development of human testis and in a large series of neoplastic/dysgenetic specimens [1].
• Taken together, this novel expression pattern of NANOG in goat preimplantation embryos suggests that NANOG could serve as marker of pluripotency in goats and may be useful in derivation and characterization of caprine ESC [11].
• Human NT2 cells, which differentiate into neurons and astrocytes, initially express and then permanently down-regulate Nanog and Oct-4 (POU5F1) [12].

Associations of NANOG with chemical compounds

• Of interest, addition of the tyrosine phosphatase inhibitor, sodium vanadate, selectively repressed Nanog transcription without any detectable changes in upstream transcriptional regulators Oct3/4 and Sox2 [8].
• Developmental expression of pluripotency determining factors in caprine embryos: Novel pattern of NANOG protein localization in the nucleolus [11].
• All three hESC lines expressed specific markers for non-differentiation (Nanog, stage-specific embryonic antigen-4 [SSEA-4], tumour-related antigen [TRA]-1-60, and TRA-1-81) and were negative for SSEA-1 [13].
• Co-immunoprecipitation and glutathione S-transferase pulldown experiments confirmed the interaction between Nanog and Sall4 [14].

Regulatory relationships of NANOG

• A reporter plasmid assay also showed that both variants of nanog modestly repressed transactivation of gata-4, whose expression is proposed to be inhibited by nanog, with comparable potency [15].
• In this context, p53 induces the differentiation of DNA-damaged ESCs by directly suppressing the expression of Nanog, which is critical for the self-renewal of ESCs [16].
• NANOG has antisense Alu elements in its 3'UTR region, making it susceptible to the regulation of other protein-coding messenger RNAs with sense Alu elements, as well as Pol-III transcribed Alus [17].

Other interactions of NANOG

• Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours [1].
• We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes [18].
• The expression of CD9, taube nuss and nanog suggests the presence of stem cells from the earliest stages of embryogenesis in adult myocardium [19].
• RESULTS: The NANOG gene and all pseudogenes except NANOGP8 are present at their expected orthologous chromosomal positions in the chimpanzee genome when compared to the human genome, indicating that their origins predate the human-chimpanzee divergence [20].
• Deletion of both WR and CD2 from NANOG completely eliminated its transactivation function [21].

Analytical, diagnostic and therapeutic context of NANOG

• Examination of global transcriptional changes upon NANOG overexpression by DNA microarray analysis reveals new markers suggested to discriminate between these populations [22].
• OCT-3/4 results were similar to those of AP-2gamma, whereas NANOG and PLAP stainings were unsuitable [23].
• Immunohistochemistry and quantitative real-time PCR analysis were used to demonstrate that NANOG is highly and specifically expressed in carcinoma in situ (CIS), embryonal carcinomas, and seminomas, but not in teratomas and yolk sac tumors [24].
• METHODS: Immunohistochemistry and quantitative polymerase chain reaction (QPCR) were used to examine the expression and gene copy number of the human NANOG gene in germ cell tumors [24].
• ESC colonies demonstrated radial organization of phosphorylated signal transducer and activator of transcription 3, Nanog, and Oct4 (among others) in the presence and absence of exogenous leukemia inhibitory factor (LIF) [25].

References