HOW A FEMALE X CHROMOSOME IS INACTIVATED
Chromosomes
differentiate men from women. A woman's somatic cells have two X chromosomes,
while a man's carry only one. If both X chromosomes and all of their genes were
to be active in women, they would have twice as many copies of the proteins
that they produce in men. This would consequently result in a disequilibrium
that would disrupt the finely balanced biochemistry of the human body
Nature ensures this
does not happen: one of the X chromosomes is completely and permanently
inactivated during a female's early development in the womb. The mechanism
responsible for this inactivation is not yet fully understood. However,
research into mice has shown that a ribonucleic acid (RNA) molecule called Xist
plays a pivotal role in the process. Several hundred copies of this molecule
attach themselves to one of the two X chromosomes. Scientists believe that
these RNA molecules dock onto other molecules which then inactivate the
chromosome. A team of researchers lead by Anton Wutz, Professor of Genetics at
ETH Zurich, have now discovered several of these inactivation molecules.
Screening to rescue
cells
To this end,
scientists used mouse stem cells, which exhibited two particular
characteristics. Firstly, like unfertilised egg cells (and in contrast to
somatic cells), they had just one instance of each chromosome. Secondly, they
were modified to a degree that allowed the scientists to continuously produce
the Xist RNA. This led to the inactivation of the single X chromosome and the
death of the cells, since the genes needed for their continued survival could
no longer be read.
In a large-scale
screening experiment using these stem cells, scientists were able to identify
which genes were important for X inactivation. It is possible to think of the
experiment as a sort of rescue operation for the stem cells that would
otherwise have died. Specifically, researchers used a virus to randomly damage
individual genes in the genetic material of a large number of stem cells .
Virus insertions that destroyed a gene, which was required for Xist RNA to
inactivate the X chromosome, the X chromosome was not inactivated, and the
corresponding cells survived.
The scientists were
thus able to isolate surviving stem cells and identify seven genes that are
central to X inactivation. One of them is called Spen. Scientists were already
aware that Spen produces a protein which allows it to bind with RNA and
essentially prevents the genes from being read. In other experiments, ETH
researchers were able to show that if a mouse cell lacks the Spen gene, the
proteins responsible for altering chromosome structure are not able to accumulate
as efficiently at the X chromosome. ETH Professor Wutz explains that further
research is required to understand exactly how this mechanism works and what
role the other recently discovered genes play in it.
Research made possible
thanks to earlier advances
"Genetic research
such as this is extraordinarily complex," says Wutz. For example, a
significant body of knowledge about mammalian genetics comes from conclusions
yielded by research into drosophilidae (fruit flies), which are a model
organism for biology and, in particular, for genetic research. Unlike mammals,
however, fruit flies have a different chromosome system that does not include X
inactivation. You cannot therefore draw on fruit-fly genetics to find gene
candidates in mammals.
According to the
professor, methodological advances made in recent years have made his research
possible. Research of this type is now possible thanks to stem cells with the
simple set of chromosomes, created by Wutz five years ago while he was still at
the University of Cambridge.
The ETH researchers
published their work in the latest issue of the scientific journal Cell
Reports. A British research team also published its findings in the same
issue. Using a different method -- RNA interference -- they discovered several
of the genes involved in X inactivation. One of them is Spen.
Slight differences in
humans
The genes for Xist and
Spen are found in humans as well. Thus, as Wutz points out, this research
offers us some insight into the human system -- at least at the theoretical
level, as mouse genetics cannot be mapped directly to humans.
A few years ago, a
team of French researchers postulated that, in addition to Xist, humans also
have another system which ensures that the single X chromosome in men and one
of the two X chromosomes in women remain active. This activating system does
not exist in mice. Due to the interplay of activating and inactivating factors,
regulation of X chromosomes in humans might therefore be more complicated than
originally thought. Geneticists wanting to understand these processes in detail
still have plenty of work ahead of them.
Chromosomes
differentiate men from women. A woman's somatic cells have two X chromosomes,
while a man's carry only one. If both X chromosomes and all of their genes were
to be active in women, they would have twice as many copies of the proteins
that they produce in men. This would consequently result in a disequilibrium
that would disrupt the finely balanced biochemistry of the human body
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