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Two coupled feedback loops explain random mono-allelic Xist upregulation at the onset of X-chromosome inactivation

MPS-Authors
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Mutzel,  Verena
Regulatory Networks in Stem Cells (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Dunkel,  Ilona
Regulatory Networks in Stem Cells (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons145411

Schulz,  Edda G.
Regulatory Networks in Stem Cells (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Mutzel, V., Okamoto, I., Dunkel, I., Saitou, M., Giorgetti, L., Heard, E., et al. (2017). Two coupled feedback loops explain random mono-allelic Xist upregulation at the onset of X-chromosome inactivation. bioRxiv: the preprint server for biology, 2017, 1-54. doi:10.1101/204909.


Cite as: https://hdl.handle.net/21.11116/0000-0000-74CB-9
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.