Chromatin and Gene Expression Group (CGEG)
Institute of Biomedical Research
University of Birmingham
United Kingdom
Head: Professor Bryan Turner
Research
The group’s work is concerned with understanding the
mechanisms by which the packaging of DNA as chromatin regulates gene expression.
Our work focuses on the major DNA-packaging proteins, the histones. These
proteins are subject to a variety of post-translational modifications, including
acetylation and methylation of defined lysine residues and phosphorylation of
specific serines.
 These modifications
are put in place through the actions of families of enzymes that add and remove
acetate, methyl and phosphate moieties. Recent evidence shows that patterns of
histone modification play a central role in control of gene expression and it
has been proposed that they constitute a histone code, or epigenetic code,
responsible for the maintenance or alteration of patterns of gene expression
through differentiation and development.
The enzymes that regulate histone modifications are
proving attractive drug targets and inhibitors of histone deacetylating enzymes
(HDACs) are now in clinical trials against a variety of cancers. The group is
involved in a phase II trial here in Birmingham to test the effectiveness of the
HDAC inhibitor sodium valproate in patients with Acute Myeloid Leukaemia (AML).
Research
in the CGEG has two main themes. Firstly, we are investigating mechanisms by
which genes are silenced (stably switched off) during early development. As a
model system we are studying the silencing of genes on one of the two X
chromosomes in female embryonic stem cells as they differentiate in culture.
 Secondly,
we are studying mechanisms by which histone deacetylase inhibitors influence the
growth and behaviour of normal and cancer cells and the roles of the deacetylases that they target in cell differentiation. Both these lines of work
involve microarray expression analysis, both to gain an overview of the effects
of differentiation and inhibitors on gene expression patterns and to identify
genes that change expression in particular ways.
Much of our work has involved the use of novel antisera
raised against modified histones or specific deacetylating enzymes and the group
has pioneered the use of antibody-based techniques for chromatin research. We
are currently attempting to develop technologies
 that
will allow us to examine epigenetic changes on key regulator genes in cells
differentiating in their native environment (niche). We have developed a novel
chromatin immunoprecipitation approach (CChIP)
that allows us to define patterns of histone modification across key genes in as
few as 100 cells (see protocols). This has allowed to compare histone marks
associated with pluripotency genes such as Nanog and Pou5f1 (Oct4) in the Inner
Cell Mass from cultured mouse embryos, with marks on the same genes in embryonic
stem cell lines. We are using this approach to examine how environmental
variables and toxins can change epigenetic marks in the early embryo in ways
that subvert normal development at later stages. The same technique offers
promise for analysis of small cell samples prepared by FACS sorting or cut from
tissue sections by laser microdissection.
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