[149806] in North American Network Operators' Group
and now for something completely different
daemon@ATHENA.MIT.EDU (bmanning@vacation.karoshi.com)
Thu Feb 16 00:17:26 2012
Date: Thu, 16 Feb 2012 05:16:18 +0000
From: bmanning@vacation.karoshi.com
To: nanog@nanog.org
Errors-To: nanog-bounces+nanog.discuss=bloom-picayune.mit.edu@nanog.org
Control of ground-state pluripotency by allelic regulation of Nanog
Nature advance online publication 12 February 2012. doi:10.1038/nature10807
Authors: Yusuke Miyanari & Maria-Elena Torres-Padilla
Pluripotency is established through genome-wide reprogramming during mammal=
ian pre-implantation development, resulting in the formation of the naive e=
piblast. Reprogramming involves both the resetting of epigenetic marks and =
the activation of pluripotent-cell-specific genes such as Nanog and Oct4 (a=
lso known as Pou5f1). The tight regulation of these genes is crucial for re=
programming, but the mechanisms that regulate their expression in vivo have=
not been uncovered. Here we show that Nanog=E2=80=94but not Oct4=E2=80=94i=
s monoallelically expressed in early pre-implantation embryos. Nanog then u=
ndergoes a progressive switch to biallelic expression during the transition=
towards ground-state pluripotency in the naive epiblast of the late blasto=
cyst. Embryonic stem (ES) cells grown in leukaemia inhibitory factor (LIF) =
and serum express Nanog mainly monoallelically and show asynchronous replic=
ation of the Nanog locus, a feature of monoallelically expressed genes, but=
ES cells activate both alleles when cultured under 2i conditions, which mi=
mic the pluripotent ground state in vitro. Live-cell imaging with reporter =
ES cells confirmed the allelic expression of Nanog and revealed allelic swi=
tching. The allelic expression of Nanog is regulated through the fibroblast=
growth factor=E2=80=93extracellular signal-regulated kinase signalling pat=
hway, and it is accompanied by chromatin changes at the proximal promoter b=
ut occurs independently of DNA methylation. Nanog-heterozygous blastocysts =
have fewer inner-cell-mass derivatives and delayed primitive endoderm forma=
tion, indicating a role for the biallelic expression of Nanog in the timely=
maturation of the inner cell mass into a fully reprogrammed pluripotent ep=
iblast. We suggest that the tight regulation of Nanog dose at the chromosom=
e level is necessary for the acquisition of ground-state pluripotency durin=
g development. Our data highlight an unexpected role for allelic expression=
in controlling the dose of pluripotency factors in vivo, adding an extra l=
evel to the regulation of reprogramming.
