The
expression of Ski-related oncogene N (SNON) prior to (left) and after (right)
the onset of differentiation
A
repressor protein that blocks differentiation-specific genes helps maintain
stem cells' ability to develop into any cell type
Researchers at the A*STAR Institute of
Medical Biology (IMB) have discovered a critical checkpoint protein that
controls when human embryonic stem cells (hESCs) begin to differentiate1.
The Nodal/Activin signaling pathway is an
important regulator of hESC fate. Signaling molecules in this pathway trigger
the downstream proteins SMAD2 and SMAD3 to activate a transcription factor
known as NANOG, as well as other core pluripotency proteins. These regulatory
factors, in turn, ensure that the self-renewing hESCs remain capable of forming
all cell types in the embryo and avoid differentiation.
When differentiation is triggered, however,
the role of this signaling axis changes, and the very same pathway begins to
drive the formation of primitive cell types, namely the mesoderm and endoderm.
To explain these contrasting effects of
Nodal/Activin signaling, a team led by the IMB’s Ray Dunn explored the role of
repressor proteins in the pathway. “We reasoned that one explanation for why
hESCs do not differentiate in the presence of Nodal/Activin is the existence of
repressor proteins that decorate the regulatory elements of differentiation
genes and turn them off,” Dunn explains. “In my lab, we identified one such
repressor that fits this bill, [it is] called SNON.”
SNON, an abbreviation of Ski-related oncogene
N, is a potent repressor of SMAD2 and SMAD3 and, as Dunn’s team showed, is
abundant in undifferentiated hESCs, but only at the promoters of
differentiation genes. At the onset of differentiation, SNON is destroyed by the
proteasome, the cell’s clean-up machinery for unwanted proteins. SNON levels
then drop precipitously (see image), which allows SMAD2 and SMAD3 to cooperate
with other transcription factors involved in the determination of cell fate,
including FoxA2. This leads to the formation of early mesoderm and endoderm,
two of the three primitive germ layers.
“Our research shows that when hESCs begin to
differentiate, SNON is targeted for degradation,” says Dunn. This finding is
consistent with many studies of cancer cell lines, which, like hESCs, retain
the ability for continuous proliferation and also have elevated levels of SNON.
One outstanding question, according to Dunn,
remains the identity of the molecules that target SNON for degradation. A
protein called ARKADIA is one suspect. ARKADIA is known to regulate SNON
stability in a cell type-dependent fashion, but its role in embryonic stem
cells remains unclear. “Follow up experiments in our lab aim to determine
whether ARKADIA acts alone or collaborates to degrade SNON in hESCs,” says
Dunn.
The A*STAR-affiliated researchers
contributing to this research are from the Institute of Medical Biology
References
- Tsuneyoshi, N., Tan, E. K., Sadasivam, A.,
Poobalan, Y., Sumi, T. et al. The SMAD2/3 corepressor SNON
maintains pluripotency through selective repression of mesendodermal genes
in human ES cells. Genes & Development 26, 2471–2476
(2012). | article
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