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While the sequencing of the human
genome, as well as the genomes of other organisms, has been a monumental
step forward in understanding how complex phenotypes arise from a
single genome, this new wealth of DNA sequence data has also created
many new challenges. Fundamental questions being addressed by the
Genome Biology program include: (1) Deciphering the complex nature
of the information encoded by our genome and how this genomic information
differs from one individual to the next. (2) How the expression of
this information is both regulated and integrated to create complex
networks needed to direct biological activities. (3) How the genome
is structurally organised to enable the above functions to be carried
out properly and to stably maintain the integrity of our genome across
generations. It is becoming clear that in addition to the simple genetic
encoding of proteins, the genome contains much more genetic information
then first realised. Developing new bioinformatic methods and employing
a comparative evolutionary approach, we are identifying new functions
for genomic sequences and uncovering novel DNA sequences that vary
between individuals, which may directly correlate with the susceptibility
of an individual to certain disease states. In terms of understanding
the connection between the information the genome contains and phenotype,
we are elucidating and comparing the regulatory architecture of gene
expression patterns in different cell types. In the nucleus of every
cell, genomic DNA forms a complex with histones and a wealth of non-histone
proteins to form a dynamic structure known as chromatin. Chromatin
is a highly modified structure with a diverse range post-translational
modifications and regions of the genome where core histones are replaced
with their variant forms. Significantly, it is believed that specific
combinations of these chromatin modifications adds an other layer
of information on top of the genetic code, referred to as the epigenetic
code, which regulates all aspects of genome function including gene
expression and organising the genome into specific structures required
for the stable inheritance of our genome e.g. the centromere. To gain
new insights into this epigenetic code and importantly its interplay
with genetic information (which is far from being understood), we
are studying its role in controlling inducible gene transcription
in the immune system and how chromatin is remodelled during mouse
embryonic stem cell differentiation necessary to establish gene expression
programs. The former study has important implications in understanding
many chronic immune diseases including autoimmunity and leukaemia.
To begin to elucidate the mechanism of how the epigenetic code regulates
genome function, we are performing structural studies on epigenetically
modified chromatin assembled in vitro. Our genome is littered with
repetitive DNA elements, such as retrotransposons, that if left unchecked
would create havoc to our genome. We are focused on understanding
the epigenetic mechanisms that keep these DNA elements silenced. New
studies will also investigate the role of small RNA molecules in this
process.
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