Homeobox protein NANOG

See NANOG (computing) for the network operators' group.

Nanog homeobox
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2KT0
Identifiers
Symbol	NANOG
External IDs	OMIM: 607937 MGI: 1919200 HomoloGene: 78027 GeneCards: NANOG Gene
Gene ontology Molecular function • DNA binding • sequence-specific DNA binding transcription factor activity • transcription corepressor activity • sequence-specific DNA binding Cellular component • nucleus • nucleoplasm • nucleolus Biological process • endodermal cell fate specification • transcription, DNA-templated • regulation of transcription, DNA-templated • cell proliferation • regulation of gene expression • stem cell maintenance • cell differentiation • somatic stem cell maintenance • regulation of cell differentiation • positive regulation of transcription from RNA polymerase II promoter • negative regulation of nucleic acid-templated transcription Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	79923	71950
Ensembl	ENSG00000111704	ENSMUSG00000012396
UniProt	Q9H9S0	Q80Z64
RefSeq (mRNA)	NM_001297698	NM_001289828
RefSeq (protein)	NP_001284627	NP_001276757
Location (UCSC)	Chr 12: 7.79 – 7.8 Mb	Chr 6: 122.71 – 122.71 Mb
PubMed search	[1]	[2]

NANOG (pron. nanOg) is a transcription factor critically involved with self-renewal of undifferentiated embryonic stem cells. In humans, this protein is encoded by the NANOG gene.

Structure

Human NANOG protein is a 305 amino acid protein with a conserved homeodomain motif that is localized to the nuclear component of cells. The homeodomain region facilitates DNA binding.

There are N-terminal, homeodomain, and C-terminal regions in human NANOG protein. Like murine NANOG, the N-terminal region of human NANOG is rich in Ser, Thr and Pro residues, and the C-terminus contains W repeats. The homeodomain in hNANOG ranges from residues 95 to 155. The conserved sequence of homeodomain are a.a. 99-100, 102, 106-107, 110, 114, 119, 121, 127-128, 132, 134, 138-140, 142-145, 147, 149, and 151-152.

Function

Transcription programs in embryonic stem cells

NANOG is a transcription factor in embryonic stem cells (ESCs) and is thought to be a key factor in maintaining pluripotency. NANOG is thought to function in concert with other factors such as POU5F1 (Oct-4) and SOX2 to establish ESC identity. These cells offer an important area of study because of their ability to maintain pluripotency. In other words, these cells have the ability to become virtually any cell of any of the three germ layers (endoderm, ectoderm, mesoderm). It is for this reason that understanding the mechanisms that maintain a cell's pluripotency is critical for researchers to understand how stem cells work; and may lead to future advances in treating degenerative diseases.

Analysis of arrested embryos demonstrated that embryos express pluripotency marker genes such as POU5F1, NANOG and Rex1. Derived human ESC lines also expressed specific pluripotency markers:

• TRA-1-60
• TRA-1-81
• SSEA4
• alkaline phosphatase
• TERT
• Rex1

These markers allowed for the differentiation in vitro and in vivo conditions into derivatives of all three germ layers.

POU5F1, TDGF1 (CRIPTO), SALL4, LECT1, and BUB1 are also related genes all responsible for self-renewal and pluripotent differentiation.

The NANOG protein has been found to be a transcriptional activator for the Rex1 promoter, playing a key role in sustaining Rex1 expression. Knockdown of NANOG in embryonic stem cells results in a reduction of Rex1 expression, while forced expression of NANOG stimulates Rex1 expression.

Current research

Molecular biology

Overexpression of Nanog in mouse embryonic stem cells causes them to self-renew in the absence of Leukemia inhibitory factor. In the absence of Nanog, mouse embryonic stem cells differentiate into visceral/parietal endoderm. Loss of Nanog function causes differentiation of mouse embryonic stem cells into other cell types.

NANOG overexpression in human embryonic stem cells enables their propagation for multiple passages during which the cells remain pluripotent. Gene knockdown of Nanog promotes differentiation, thereby demonstrating a role for these factors in human embryonic stem cell self-renewal.

It has been shown that the tumour suppressor p53 binds to the promoter of NANOG and suppresses its expression after DNA damage in mouse embryonic stem cells. p53 can thus induce differentiation of embryonic stem cells into other cell types which undergo efficient p53-dependent cell-cycle arrest and apoptosis.

Nanog transforms NIH3T3 cells. By using DNA microarray to find the transcription targets of Nanog, Nanog regulated genes have been identified. Some of these target genes explain the transformation of NIH3T3 cells.

GATA6 and Nanog have been linked due to the similar cellular differentiation of ES cells in their absence, which leads to the hypothesis that Nanog may prevent ectodermal growth via repressing GATA6.

Yamanaka et al., demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Of these four factors it has been shown that Nanog was dispensable for such induction in this cell system.

Clinical medicine

NANOG may be useful in the immunohistochemical diagnosis of tumors. NANOG is expressed in germ cells of the fetus and in some germ cell tumors of the gonads and central nervous system (CNS). Expression of NANOG by immature teratoma and choriocarcinoma is unknown. Among tumors usually found in the CNS, NANOG is expressed by germinoma (a germ cell tumor histologically identical to seminoma and dysgerminoma) but not by pineoblastoma, lymphoma, pituitary adenoma and gliomas; expression of NANOG by other germ cell tumors of the CNS is unknown. Recent studies have suggested that NANOG could define cancer stem cells in several types of solid tumors such as colorectal cancer

Evolutionary biology

Humans and chimpanzees share ten NANOG pseudogenes, all in the same places: one duplication pseudogene and nine retropseudogenes. Of the nine shared NANOG retropseudogenes, two lack the poly-(A) tails characteristic of most retropseudogenes, indicating copying errors occurred during their creation. Due to the high improbability that the same pseudogenes (copying errors included) would exist in the same places in two unrelated genomes, evolutionary biologists point to NANOG and its pseudogenes as providing formidable evidence of common descent between humans and chimpanzees.

Biophysics

Based on high-resolution nucleosome mapping in mouse embryonic stem cells, it has been proposed that as a pioneering factor, Nanog is able to bind the DNA inside the nucleosome in vivo.

Name

Professor Ian Chambers (currently of the MRC Centre for Regenerative Medicine, The University of Edinburgh, UK) who isolated the mouse Nanog gene said: "Nanog seems to be a master gene that makes embryonic stem cells grow in the laboratory. In effect this makes stem cells immortal. Being Scottish, I therefore chose the name after the Tír na nÓg legend."

See also

• Enhancer
• Histone
• Oct-4
• Pribnow box
• Promoter
• RNA polymerase
• Brachyury
• Transcription factors
• Gene regulatory network
• Bioinformatics

External links

• NANOG protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• Nanog protein, mouse at the US National Library of Medicine Medical Subject Headings (MeSH)
• FactorBook NANOG
• Discovery reveals more about stem cells' immortality