Homeobox protein NANOG

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Template:Dablink Template:PBB/79923 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.[1][2]

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.

Relation to other pluripotency factors

File:Transcription programs in stem cells..jpg
Transcription programs in embryonic stem cells

NANOG is a transcription factor in embryonic stem cells (ESCs) and is a key factor in maintaining pluripotency. NANOG functions in concert with other core pluripotency factors such as POU5F1 (Oct-4) and SOX2 to establish ESC identity.

Undifferentiated, pluripotent embryonic stem cells express Nanog and other 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

POU5F1, TDGF1 (CRIPTO), SALL4, LECT1, and BUB1 are also related genes all responsible for self-renewal and pluripotent differentiation.[3]


Function in Stem Cells

Overexpression of Nanog in mouse embryonic stem cells allows them to self-renew in the absence of Leukemia inhibitory factor and loss of Nanog function causes differentiation of mouse embryonic stem cells into differentiated cell types.[4] Additionally, Nanog-deficient mouse embryonic stem cells differentiate into visceral/parietal endoderm and Nanog-deficient cells of the inner cell mass obtained from preimplantation embryos go on to generate only extra embryonic cells and no epiblast.[1][2] These results are consistent with Nanog repressing the formation of primitive endoderm cells.[5] Nanog is therefore crucial for maintaining pluripotency in both populations of cells. Interestingly, Nanog expression is not consistent in embryonic stem cell populations and is heterogenous, meaning that some cells have either higher or lower expression of Nanog that are constantly fluctuating. Populations of Nanog-high cells are pluripotent and can differentiate into all three germ layers. However, populations of Nanog-low cells form only extra embryonic endoderm cells and are therefore confined to lineage-specific cell fates. [6]

NANOG overexpression in human embryonic stem cells enables their propagation for multiple passages during which the cells remain pluripotent.[7] Gene knockdown of Nanog promotes differentiation, thereby demonstrating a role for these factors in human embryonic stem cell self-renewal as well.[8]

Regulation and Interactions of Nanog

  • GATA6 and is likely negatively regulated by Nanog[10] and it is hypothesized that Nanog may prevent ectodermal growth via repressing GATA6.[11] Nanog binds to the proximal promoter region of Gata6 and can reduce Gata6 expression by doing so. Nanog-low populations of embryonic stem cells have higher expression of Gata6 and therefore more differentiated character.[12]
  • 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.[4]


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.[15]

Current Research and applications

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[16] and central nervous system (CNS).[17][18] 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;[17] 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 [19]

Role in Reprogramming

Nanog has also been shown to be involved in the production of induced pluripotent stem cells, through its use as one of the Thomson reprogramming factors, along with Oct-4, Sox2, and Lin28. Nanog was included as a reprogramming factor due to its significantly beneficial effect on reprogramming efficiency.[20] Together, these factors were able to reprogram human fibroblast cells into induced cells that express the traits and marks of pluripotency.

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.[21]

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.[22]

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."[23]

See also

References

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