aggregation of proteins randomly determines which of the two X
chromosomes in a woman's cell will remain active, and which one will
stay silenced, according to a new physical model.
In all placental
mammals, the females of the species have two versions of the X
chromosomes while males have just one X, plus a Y chromosome. To
avoid overexpression of X-chromosome genes, female cells must
virtually shut down one of their X's. X chromosomes are able to
wrap themselves up in a goo of RNA -- produced by one of their
genes, called XIST -- inhibiting the expression of all of their
But until recently, it was not known how a female's cells
know that they have two X's, how they choose which one to shut down,
or how they keep exactly one active. Experiments in mice -- the
results presumably apply to other mammals -- have shown that during
early development, each embryo cell has a 50-50 chance of shutting
down one X or the other.
Recently it has been proposed that an X
remains active when certain proteins aggregate at a specific spot on
the chromosome, shutting down its "suicide gene" XIST. But it
remained unclear why proteins floating in the nucleus would
aggregate around one of the chromosome, but not around the other --
an example of what physicists call spontaneous symmetry breaking.
Now an upcoming paper in Physical Review Letters describes a
statistical-mechanics model for the proteins' aggregation that would
explain this phenomenon. The model relies on a key discovery
published last year, namely that in females the two X chromosomes
line up next to each other right at the time when one of them is due
to be silenced. For a critical value of the protein's binding
energies, the authors show, there is a high probability that exactly
one aggregate will form in the vicinity of the two chromosomes. The
aggregate will quickly bind to one of the X's, shutting down its
XIST gene and thus preventing the chromosome from silencing itself.
The model also explains how cells would "count" their X's. In males,
the protein complex would only have one chromosome to bind to, so it
would save the single X from self-silencing. On non-sexual
chromosomes, a similar mechanism could also determine which of two
versions of certain genes is expressed and which one is silenced.
Nicodemi and Prisco, to appear in Physical Review Letters
University of Naples "Federico II"
Na Xu et al., Science, 24 February 2006
Bacher et al., Nature Cell Biology, March 2006
Donohoe et al., Molecular Cell, January 12, 2007