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Free keywords:
X-chromosome inactivation, gene-regulatory networks, mathematical modelling, feedback loops, systems biology, mono-allelic expression, transcriptional interference, antisense transcription
Abstract:
In female mammal
s, dosage compensation for X-linked genes
is ensured through
random X-chromosome inactivation, which
is initiated by mono-allelic up-regulation of
Xist
.
We
use mathematical modeling
to identify the regulatory principles
required
to
establish the
mono-allelic and female-specific
Xist
expression pattern
and test model
predictions experimentally.
A
cis
-acting positive feedback, which in mice is mediated by
mutual repression of
Xist
and its antisense transcript
Tsix
, together with a
trans
-acting
negative feedba
ck
are sufficient to
explain mono-allelic
Xist
up-regulation.
The
model
can reproduce data from several mutant, aneuploid and polyploid murine
cell
lines
and
explain
s
Xist
expression patterns in other mammalian species. Furthermore,
it predicts
that transient
, reversible
bi-allelic
Xist
expression
is not
restricted to
rabbits and
humans but can also occur in mice, which we
indeed
confirm
to occur
in
mouse
embryos.
Overall, our study
provides a conceptual framework of the molecular
mechanisms required to initiate random X-chromosome inactivation.
