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Homeobox protein NANOG (hNanog) is a
transcriptional Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...
factor that helps embryonic stem cells (ESCs) maintain pluripotency by suppressing cell determination factors. hNanog is encoded in humans by the ''NANOG'' gene. Several types of cancer are associated with ''NANOG''.


Etymology

The name NANOG derives from
Tír na nÓg In Irish mythology Tír na nÓg (; "Land of the Young") or Tír na hÓige ("Land of Youth") is one of the names for the Celtic Otherworld, or perhaps for a part of it. Tír na nÓg is best known from the tale of Oisín and Niamh. Other Old Iri ...
(Irish for "Land of the Young"), a name given to the Celtic Otherworld in Irish and Scottish mythology.


Structure

The human hNanog protein coded by the ''NANOG'' gene, consists of 305 amino acids and possesses 3 functional domains: the N-terminal domain, the C- terminal domain, and the conserved
homeodomain A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. For instance, mutations in a homeobox may change large-scale anatomical features of the full-g ...
motif. The homeodomain region facilitates DNA binding. The ''NANOG'' is located on chromosome 12, and the mRNA contains a 915 bp open reading frame (ORF) with 4 exons and 3 introns. The N-terminal region of hNanog is rich in serine, threonine and proline residues, and the C-terminus contains a tryptophan-rich domain. The homeodomain in hNANOG ranges from residues 95 to 155. There are also additional NANOG genes (NANOG2, NANOG p8) which potentially affect ESCs' differentiation. Scientists have shown that ''NANOG'' is fundamental for self-renewal and pluripotency, and NANOG p8 is highly expressed in cancer cells.


Function

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 Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gastru ...
, 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. NANOG has been described to be expressed in the posterior side of the epiblast at the onset of gastrulation. There, NANOG has been implicated in inhibiting embryonic hematopoiesis by repressing the expression of the transcription factor ''Tal1''. In this embryonic stage, NANOG represses ''Pou3f1'', a transcription factor crucial for the anterior-posterior axis formation. Analysis of arrested embryos demonstrated that embryos express pluripotency marker genes such as POU5F1, NANOG and
Rex1 Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells. In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state. As the cells begi ...
. Derived human ESC lines also expressed specific pluripotency markers: *TRA-1-60 *TRA-1-81 *SSEA4 *alkaline phosphatase *TERT *
Rex1 Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells. In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state. As the cells begi ...
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 Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells. In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state. As the cells begi ...
promoter, playing a key role in sustaining
Rex1 Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells. In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state. As the cells begi ...
expression. Knockdown of NANOG in embryonic stem cells results in a reduction of
Rex1 Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells. In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state. As the cells begi ...
expression, while forced expression of NANOG stimulates
Rex1 Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells. In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state. As the cells begi ...
expression. Besides the effects of NANOG in the embryonic stages of life, ectopic expression of NANOG in the adult stem cells can restore the proliferation and differentiation potential that is lost due to organismal aging or cellular senescence.


Clinical significance


Cancer

NANOG is highly expressed in cancer stem cells and may thus function as an oncogene to promote carcinogenesis. High expression of NANOG correlates with poor survival in cancer patients. Recent research has shown that the localization of NANOG and other transcription factors have potential consequences on cellular function. Experimental evidence has shown that the level of NANOG p8 expression is elevated specially in cancer cells, which mean that NANOG p8 gene is a critical member in (CSCs) Cancer stem cells, so knocking it down could reduce the cancer malignancy.


Diagnostics

NANOG p8 gene has been evaluated as a prognostic and predictive cancer biomarker.


Cancer stem cells

Nanog is a transcription factor that controls both self-renewal and pluripotency of embryonic stem cells. Similarly, the expression of Nanog family proteins is increased in many types of cancer and correlates with a worse prognosis.


Evolution

Humans and
chimpanzees The chimpanzee (''Pan troglodytes''), also known as simply the chimp, is a species of great ape native to the forest and savannah of tropical Africa. It has four confirmed subspecies and a fifth proposed subspecies. When its close relative the ...
share ten NANOG pseudogenes (NanogP2-P11) during evaluation, two of them are located on the X chromosome and they characterized by the 5’ promoter sequences and the absence of introns as a result of mRNA retrotransposition 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 that 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 Evolutionary biology is the subfield of biology that studies the evolutionary processes ( natural selection, common descent, speciation) that produced the diversity of life on Earth. It is also defined as the study of the history of life fo ...
point to NANOG and its pseudogenes as providing
evidence of common descent Evidence of common descent of living organisms has been discovered by scientists researching in a variety of disciplines over many decades, demonstrating that all life on Earth comes from a single ancestor. This forms an important part of the ev ...
between humans and chimpanzees.


See also

* Enhancer * Histone * Oct-4 * Pribnow box * Promoter *
RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens the ...
*
Brachyury T-box transcription factor T, also known as Brachyury protein, is encoded for in humans by the ''TBXT'' gene. Brachyury functions as a transcription factor within the T-box family of genes. Brachyury homologs have been found in all bilaterian a ...
*
Transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
* Gene regulatory network *
Bioinformatics Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combine ...


References


Further reading

* * * * * * * * * * * * * * * * * *


External links

* * * * *
Discovery reveals more about stem cells' immortality
{{Transcription factors, g3 Gene expression Oncology Transcription factors