Nanog (transcription factor)
Encyclopedia
NANOG is a transcription
factor critically involved with self-renewal of undifferentiated embryonic stem cell
s. In humans, this protein is encoded by the NANOG gene
.
There are N-terminal, homeodomain, and C-terminal regions in human NANOG protein. Like murine NANOG, N-terminal region of human NANOG is rich in Ser, Thr and Pro residues and 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.
s (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
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:
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.
. 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.
s of the fetus
and in some germ cell tumor
s 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 glioma
s; expression of NANOG by other germ cell tumors of the CNS is unknown.
s and chimpanzee
s share ten NANOG pseudogene
s, all in the same places: one duplication pseudogene and nine retropseudogenes. Of the nine shared NANOG retropseudogenes, two lack the poly-(A) tail
s 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 genome
s, evolutionary biologists point to NANOG and its pseudogenes as providing formidable evidence of common descent between humans and chimpazees.
, 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."
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
factor critically involved with self-renewal of undifferentiated embryonic stem cell
Embryonic stem cell
Embryonic stem cells are pluripotent stem cells derived from the inner cell mass of the blastocyst, an early-stage embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells...
s. In humans, this protein is encoded by the NANOG gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
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, N-terminal region of human NANOG is rich in Ser, Thr and Pro residues and 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 gene expressed in embryonic stem cellEmbryonic stem cell
Embryonic stem cells are pluripotent stem cells derived from the inner cell mass of the blastocyst, an early-stage embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells...
s (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
Oct-4 also known as POU5F1 is a protein that in humans is encoded by the POU5F1 gene. Oct-4 is a homeodomain transcription factor of the POU family. This protein is critically involved in the self-renewal of undifferentiated embryonic stem cells...
and SOX2
SOX2
SRY -box 2, also known as SOX2, is a transcription factor that is essential to maintain self-renewal of undifferentiated embryonic stem cells....
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
Endoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and mesoderm , with the endoderm as the intermost layer...
, ectoderm
Ectoderm
The "ectoderm" is one of the three primary germ cell layers in the very early embryo. The other two layers are the mesoderm and endoderm , with the ectoderm as the most exterior layer...
, mesoderm
Mesoderm
In all bilaterian animals, the mesoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and endoderm , with the mesoderm as the middle layer between them.The mesoderm forms mesenchyme , mesothelium, non-epithelial blood corpuscles and...
). 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
Oct-4
Oct-4 also known as POU5F1 is a protein that in humans is encoded by the POU5F1 gene. Oct-4 is a homeodomain transcription factor of the POU family. This protein is critically involved in the self-renewal of undifferentiated embryonic stem cells...
, 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
Oct-4
Oct-4 also known as POU5F1 is a protein that in humans is encoded by the POU5F1 gene. Oct-4 is a homeodomain transcription factor of the POU family. This protein is critically involved in the self-renewal of undifferentiated embryonic stem cells...
, TDGF1 (CRIPTO), SALL4, LECT1, and BUB1 are also related genes all responsible for self-renewal and pluripotent differentiation.
Molecular biology
Overexpression of Nanog in mouse embryonic stem cells causes them to self-renew in the absence of Leukemia inhibitory factorLeukemia inhibitory factor
Leukemia inhibitory factor, or LIF, an interleukin 6 class cytokine, is a protein in cells that affects cell growth and development.-Function:LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells...
. 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
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Nanog transforms NIH3T3 cells
3T3 cells
3T3 cells come from a cell line established in 1962 by two scientists then at the Department of Pathology in the New York University School of Medicine, George Todaro and Howard Green. The 3T3 cell line has become the standard fibroblast cell line...
. By using DNA microarray
DNA microarray
A DNA microarray is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome...
to find the transcription targets of Nanog, Nanog regulated genes have been identified. Some of these target genes explain the transformation
Transformation (genetics)
In molecular biology transformation is the genetic alteration of a cell resulting from the direct uptake, incorporation and expression of exogenous genetic material from its surroundings and taken up through the cell membrane. Transformation occurs naturally in some species of bacteria, but it can...
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
Induced pluripotent stem cell
Induced pluripotent stem cells, commonly abbreviated as iPS cells or iPSCs are a type of pluripotent stem cell artificially derived from a non-pluripotent cell, typically an adult somatic cell, by inducing a "forced" expression of specific genes....
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 cellGerm cell
A germ cell is any biological cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate near the gut of an embryo and migrate to the developing gonads. There, they undergo cell division of two types, mitosis and meiosis, followed by...
s of the fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
and in some germ cell tumor
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
s of the gonads and central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS). Expression of NANOG by immature teratoma
Teratoma
A teratoma is an encapsulated tumor with tissue or organ components resembling normal derivatives of all three germ layers. There are rare occasions when not all three germ layers are identifiable...
and choriocarcinoma
Choriocarcinoma
Choriocarcinoma is a malignant, trophoblastic and aggressive cancer, usually of the placenta. It is characterized by early hematogenous spread to the lungs...
is unknown. Among tumors usually found in the CNS, NANOG is expressed by germinoma
Germinoma
A germinoma is a type of germ cell tumor which is not differentiated upon examination. It may be benign or malignant.-Classification:The term germinoma most often has referred to a tumor in the brain that has a histology identical to two other tumors: dysgerminoma in the ovary and seminoma in the...
(a germ cell tumor histologically identical to seminoma and dysgerminoma
Dysgerminoma
A dysgerminoma is a type of germ cell tumor; it usually is malignant and usually occurs in the ovary.A tumor of the identical histology but not occurring in the ovary may be described by an alternate name: seminoma in the testis or germinoma in the central nervous system or other parts of the...
) but not by pineoblastoma, lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
, pituitary adenoma
Pituitary adenoma
Pituitary adenomas are tumors that occur in the pituitary gland, and account for about 15% of intracranial neoplasms. Tumors which exceed 10 mm in size are defined as macroadenomas, and those smaller than 10 mm are referred to as microadenomas...
and glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
s; expression of NANOG by other germ cell tumors of the CNS is unknown.
Evolutionary biology
HumanHuman
Humans are the only living species in the Homo genus...
s and chimpanzee
Chimpanzee
Chimpanzee, sometimes colloquially chimp, is the common name for the two extant species of ape in the genus Pan. The Congo River forms the boundary between the native habitat of the two species:...
s share ten NANOG pseudogene
Pseudogene
Pseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...
s, all in the same places: one duplication pseudogene and nine retropseudogenes. Of the nine shared NANOG retropseudogenes, two lack the poly-(A) tail
Polyadenylation
Polyadenylation is the addition of a poly tail to an RNA molecule. The poly tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In eukaryotes, polyadenylation is part of the process that produces mature messenger RNA for translation...
s 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 genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
s, evolutionary biologists point to NANOG and its pseudogenes as providing formidable evidence of common descent between humans and chimpazees.
Name
Professor Ian Chambers (currently of the Centre for Regenerative Medicine, The University of EdinburghUniversity of Edinburgh
The University of Edinburgh, founded in 1583, is a public research university located in Edinburgh, the capital of Scotland, and a UNESCO World Heritage Site. The university is deeply embedded in the fabric of the city, with many of the buildings in the historic Old Town belonging to the university...
, 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
- EnhancerEnhancer (genetics)In genetics, an enhancer is a short region of DNA that can be bound with proteins to enhance transcription levels of genes in a gene cluster...
- HistoneHistoneIn biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
- Oct-4Oct-4Oct-4 also known as POU5F1 is a protein that in humans is encoded by the POU5F1 gene. Oct-4 is a homeodomain transcription factor of the POU family. This protein is critically involved in the self-renewal of undifferentiated embryonic stem cells...
- Pribnow boxPribnow boxThe Pribnow box is the sequence TATAAT of six nucleotides that is an essential part of a promoter site on DNA for transcription to occur in bacteria...
- Promoter
- RNA polymeraseRNA polymeraseRNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
- BrachyuryBrachyuryBrachyury is a protein that in humans is encoded by the T gene. Brachyury is a transcription factor within the T-box complex of genes. It has been found in all bilaterian animals that have been screened, and is also present in the cnidaria.-History:...
- Transcription factors
- Gene regulatory networkGene regulatory networkA gene regulatory network or genetic regulatory network is a collection of DNA segments in a cell whichinteract with each other indirectly and with other substances in the cell, thereby governing the rates at which genes in the network are transcribed into mRNA.In general, each mRNA molecule goes...
- BioinformaticsBioinformaticsBioinformatics is the application of computer science and information technology to the field of biology and medicine. Bioinformatics deals with algorithms, databases and information systems, web technologies, artificial intelligence and soft computing, information and computation theory, software...
- NANOGPubMedPubMed is a free database accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez information retrieval system...