Researchers have discovered a
strong physical gene interaction network that is responsible for
holding genes in a silencing grip during early development.
In the same way that people can
interact with others in close proximity, say within the same room,
or others millions of miles apart, there are also short- and
long-range interactions within the genome forming a
three-dimensional configuration where different parts of the genome
come into contact with each other.
The research presents how key
decision-making genes which specify the embryo's blueprint for
subsequent development are physically clustered in the nucleus of
embryonic stem cells and maintained in a silent state.
The different cell types forming an
embryo are derived from embryonic stem cells (ESCs). These cells
are self-renewing and are maintained in an undifferentiated state
meaning that they have the potential to become any cell type in the
body.
To become a specific cell type,
embryonic stem cells progress along a developmental pathway, losing
their stem cell characteristics and gaining new features. At a
genomic level, assuming a specialised cellular identity reflects
the switching on of appropriate developmental genes. Conversely,
maintaining a stem cell identity requires the repression of
developmental genes.
Using a novel technique developed
at the Babraham Institute, the researchers identified an unusually
strong 3D network of developmental genes in ESCs. These genes
encode proteins that establish the embryo's body plan and direct
organ development. As an ESC, you don't want these instructions
being read at this stage and so to prevent this, the genes are
clustered together and silenced.
The research showed that at the
heart of this repression is a protein complex called Polycomb
repressive complex (PRC1), a master regulator of ESC genome
architecture. The research therefore establishes a mechanism,
acting by physical interaction between specific genes and PRC1,
which effectively holds genes in a silenced state. This prevents
their expression in ESCs and so ensures maintenance of the
undifferentiated state.
The researchers propose that the
selective release of genes from this network leads to their
expression and thus controls early development decisions that start
the stem cell along the road to becoming a defined cell type.
Lastly, de-regulation of Polycomb complexes has been shown to be
the cause of several cancers and developmental disorders
emphasising the importance of understanding Polycomb-mediated gene
repression in development and disease.
Dr Sarah Elderkin of the Babraham
Institute said: "Analysing the genome-wide connections of 22,225
promoters in the genome of mouse embryonic stem cells allowed us to
identify a sub-set of nearly 100 promoters which form the strongest
interaction network seen in the entire genome.
"This is exciting because the
members of this sub-set encode early developmental regulators which
define what the embryonic stem cell will become. This research
uncovers a mechanism for how inappropriate expression of
developmental genes is prevented and also suggests how genes are
freed from this silencing in order for normal embryonic development
to proceed."
The paper, Polycomb repressive complex PRC1 spatially constrains the mouse
embryonic stem cell genome, is published in Nature
Genetics.
Source: Babraham Institute