Key gene giving embryonic stem cells ability to differentiate into
any cell identified
By Catarina Amorim (catarina.amorim at linacre.ox.ac.uk)
14 July 2009
A gene crucial for giving embryonic stem cells their ability to
differentiate into any type of cell (pluripotency) has been discovered
by an international team of researchers from the US, Portugal and
Israel. The gene — called Chd1 — seems to act by maintaining the genetic
material open and, in this way, poised to express any gene. The findings
have been published in the latest issue of the journal Nature
Chd1 is also shown to be fundamental when re-activating
differentiated tissue cells in order to create new stem cells. The
discovery has implications, not only for a better understanding of stem
cells unique characteristics, but also for the process of obtaining them
from tissue-specific cells avoiding all the problems associated with
embryonic stem cells.
Chromatin — which is the combination of DNA and protein that when
condensed form chromosomes — is organized in two forms: with the genetic
material tightly packed, so that genes are hidden, unavailable to be
activated in what is called heterochromatin, or as euchromatin, in which
case the chromosomal material is open and accessible to the cell
machinery involved in gene expression.
Different cells have different open/close areas depending on which
genes are needed for the cell to perform its function. Stem cells, on
the other hand, are known to have their chromosomal material largely
open and this has been suggested to be behind their pluripotency but so
far nothing has been proved.
Alexandre Gaspar Maia, Miguel Ramalho Santos and colleagues at the
University of California, San Francisco and Los Angeles, the Centre for
Neuroscience and Cell Biology, at the University of Coimbra, Portugal
and the Hebrew University of Jerusalem in Israel have been trying to
understand better the molecular mechanisms behind stem cells’ unique
characteristics and, just recently, identified several molecules found
in much higher quantities in pluripotent cells.
From these, one called Chd1 seemed particularly interesting and the
work now published investigates a potential link between this gene and
embryonic stem cell pluripotency.
For this, the researchers used RNA interference (RNAi), a method that
allows silencing a specific gene and — by following the changes on the
target cell — identifying its function. In fact, gene expression starts
by converting the DNA information into a RNA molecule, which then serves
as blueprint for the corresponding protein and RNAi acts by binding (so
stopping it half way) to the RNA of the gene to be silenced.
In their study Gaspar Maia and colleagues silence Chd1 in mouse
embryonic stem (ES) cells to find that not only the cells divide much
less but also lose capacity to form primordial tissues while acquiring
markers of neural cells so, apparently, losing their undifferentiated
state and, consequently, also their pluripotency in the absence of Chd1.
Further investigation showed that the Chd1 protein generally binds to
euchromatic regions (active regions) in ES cells, and that, when the
Chd1 gene is turned off, ES cells have much less euchromatin (so less
open, available areas).
Next Miguel Ramalho Santos’ team investigated the role of Chd1 in
Induced Pluripotent Stem Cells (or iPS cells). iPS cells are stem cells
obtained by re-activating the pluripotency of differentiated tissue
cells and are ailed as the alternative to the political problems of ES
cells. The fact that they are relatively easy to obtain, being
sufficient to over-activated four genes — Oct4, Sox2, Klf4 and cMyc —
all involved in switching on and off several others, has also
contributed to their overgrowing importance as a future therapeutic tool
This time the researchers used RNAi to silence Chd1 in already
differentiated cells, which then they passed through the iPS induction
protocol, to find that the number of reprogrammed ES cells obtained was
drastically reduced in comparison to those from normal Chd1 cells
showing, that also here Chd1 was crucial for pluripotency.
In conclusion, Gaspar Maia and colleagues show that Chd1 is crucial
to maintain stem cells’ pluripotency but also to maintain their
chromatin open – so keeping the genes poised to be expressed –
suggesting that the two factors are linked. Finally, they also show that
Chd1 is crucial for the reprogramming of iPS cells.
This last fact is particularly important because while the use of
embryonic stem cells is limited — not only by the ethical disagreements
behind their origins but also by the fact that they are not, by norm,
related to the patients in which they are to be used — iPS cells can be
“done by measure” and, when free from the technical problems that now
limit their use in humans, have an almost unlimited potential.
In fact, theoretically iPS could be used to study normal and diseased
tissue formation, new medication and disease in general, but also cases
of specific patients or to supply these with new healthy cells and
tissues without rejection problems. This already has been shown in mice
where these cells have been used to treat diseases as diverse as sick
cell anaemia (where red blood cells have bizarre shapes and, as result,
very short lives) and Parkinson’s disease
But for iPS cells eventually be used in humans it is crucial to
understand the mechanisms behind pluripotency and the work of Gaspar
Maia and colleagues is an important step in that direction.
Also, one of the fundamental questions when developing protocols to
create iPS cells is to assure that they are “real” stem cells so they
can become part of the body metabolism without creating disease. By
showing that both ES and iPS cells depend on Chd1 to stay pluripotent
Gaspar Maia’s work supports the idea that research to produce new stem
cells is going on the right direction.
Finally, although all this work has been done in mice, in humans Chd1
is found in much higher quantities on ES cells than on differentiated
cells, suggesting that Chd1-associated pluripotency is also used in
1. Maia AG, Sontos MR et al. Chd1 regulates open chromatin
and pluripotency of embryonic stem cells. Nature, 460, 7252, 9
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