Homeobox protein NANOG

NANOG (pron. nanOg) is a transcription factor critically involved with self-renewal of undifferentiated is_associated_with::embryonic stem cells. In humans, this protein is encoded by the NANOG is_associated_with::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 is_associated_with::homeodomain region facilitates DNA binding.

There are N-terminal, is_associated_with::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
NANOG is a transcription factor in is_associated_with::embryonic stem cells (ESCs) and is thought to be a key factor in maintaining is_associated_with::pluripotency. NANOG is thought to function in concert with other factors such as POU5F1 (Oct-4) and is_associated_with::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 (is_associated_with::endoderm, is_associated_with::ectoderm, is_associated_with::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 is_associated_with::Rex1. Derived human ESC lines also expressed specific pluripotency markers:
 * TRA-1-60
 * TRA-1-81
 * SSEA4
 * alkaline phosphatase
 * TERT
 * is_associated_with::Rex1

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

POU5F1, TDGF1 (CRIPTO), is_associated_with::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 is_associated_with::Rex1 promoter, playing a key role in sustaining is_associated_with::Rex1 expression. Knockdown of NANOG in is_associated_with::embryonic stem cells results in a reduction of is_associated_with::Rex1 expression, while forced expression of NANOG stimulates is_associated_with::Rex1 expression.

Molecular biology
Overexpression of Nanog in mouse embryonic stem cells causes them to self-renew in the absence of is_associated_with::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 is_associated_with::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 is_associated_with::apoptosis.

Nanog transforms NIH3T3 cells. By using is_associated_with::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 is_associated_with::immunohistochemical diagnosis of tumors. NANOG is expressed in is_associated_with::germ cells of the is_associated_with::fetus and in some is_associated_with::germ cell tumors of the is_associated_with::gonads and is_associated_with::central nervous system (CNS). Expression of NANOG by immature teratoma and is_associated_with::choriocarcinoma is unknown. Among tumors usually found in the CNS, NANOG is expressed by is_associated_with::germinoma (a germ cell tumor histologically identical to is_associated_with::seminoma and is_associated_with::dysgerminoma) but not by is_associated_with::pineoblastoma, is_associated_with::lymphoma, is_associated_with::pituitary adenoma and is_associated_with::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
is_associated_with::Humans and is_associated_with::chimpanzees share ten NANOG is_associated_with::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 is_associated_with::genomes, evolutionary biologists point to NANOG and its pseudogenes as providing formidable is_associated_with::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 is_associated_with::pioneering factor, Nanog is able to bind the DNA inside the nucleosome in vivo.

Name
Professor Ian Chambers (currently of the is_associated_with::MRC Centre for Regenerative Medicine, The is_associated_with::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."