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Nanog : a dosage effect to regulate cell pluripotency

Nanog expression switch from mono to biallelic.
Nanog expression is visualized thanks to colored markers. Green and red markers are showing a monoallelic expression. The yellow color is visible when the two alleles are expressed (biallelic expression)
Left (LIF): Most cells are red and green: Nanog expression is mainly monoallelic.
Right (2i.LIF): Most cells are yellow: Nanog expression is mainly biallelic in cells in a “stable” pluripotent state.

Control of ground-state pluripotency by allelic regulation of Nanog.

Miyanari Y(1), Torres-Padilla ME.

Nature Feb. 12, 2012

Feb. 12, 2012

Stability of cell pluripotency is a key issue to maintain efficiently stem cells for regenerative medicine. Researchers from Maria-Elena Torres-Padilla’s team at the French Institute of Genetics and Molecular and Cellular Biology (IGBMC, Strasbourg) have shown that pluripotency state is under control of an allelic regulation of the Nanog transcription factor. These results published online on the 12th of February in Nature are bringing to the light new mechanisms of pluripotency regulation for a better understanding of cell reprogramming.


Gene expression: when an allele goes it alone
Our characters come from the expression of our genes. Each gene comes from two versions, called “alleles”: one coming from the father, the other coming from the mother. In general, both are expressed, characters of the child resulting from the combination of the two versions (one may dominate afterwards when expressed). 
For most of our 30.000 genes, the expression is biallelic ; but for some around 60 genes, the expression may be mono-allelic, meaning that only one allele is expressed, generally coming from a “parental genomic imprinting”.

Embryo formation : From pluripotent to differenciated cells
After fertilization, early embryos transiently acquire pluripotency to be up to produce different kind of tissues. In this reprogramming process, embryos give rise to pluripotent “epiblast”. The reprogramming event involves many transcription factors. Among them, Nanog is known to be essential for acquisition of pluripotency but mechanisms of regulation of its expression have not already been addressed. Researchers from Maria-Elena Torres-Padilla team have focused on this transcription factor because they had noticed that its expression was mainly mono-allelic (i.e. that only one of two Nanog alleles was expressed) during early embryonic stages. They found that Nanog expression switches from mono-allelic in early embryos to bi-allelic at the “epiblast” state. Its expression is then reversed to mono-allelic after the implantation of the embryo, concomitant with the cell differentiation. This study shows that tight control of Nanog dosage is crucial for reprogramming, this dosage itself is under control of an allelic-regulation. Furthermore, using time-lapse imaging, they have brought to light the temporal dynamics of Nanog expression. Unlike most known monoallelic genes, the authors show that Nanog expression can switch between alleles, raising the possibility of a rather unique regulatory mechanism.

Pluripotency is largely explored since its control would efficiently help to produce new tissues and organs. These new results suggest that the activation of the second allele of Nanog would have a key-role in achieving pluripotency. They are opening new fields of investigation to generate stable induced Pluripotent Stem (iPS) cells for regenerative medicine.

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