Defining an early transcriptional response to histone deacetylase inhibitors: regulation by chromatin and effects on cell survival (Turner, Nightingale, Halsall)
Drugs that inhibit a family of enzymes known as histone deacetylases (HDACs) are undergoing clinical trials against a variety of cancers. While they have been found to be remarkably effective against a few rare cancers, they are much less effective against the most common cancers.
We will test the hypothesis, based on our preliminary data, that resistance to HDAC inhibitors in both normal cells and most cancers, is due to an ancient, evolutionarily conserved defence mechanism that serves to protect the cell’s carefully regulated patterns of gene expression from the disruptive effects of environmental enzyme inhibitors. Understanding how this defence mechanism works will point the way to treatments that can make tumour cells more sensitive to existing HDAC inhibitors.
Exploring the metaphase epigenome in normal and leukaemic cells (Turner, Rutledge, Terrenoire)
When the cell divides (ie. at mitosis) the chromosomes become highly compacted and can be seen with a light microscope. We have devised a method for staining these chromosomes with antibodies to particular family of proteins that gives each chromosome its own distinctive pattern of bright and dim bands. Our continuing work will use both microscopy and molecular biology/biochemistry to ask how these bands relate to the function of genes aligned along the chromosome, whether the banding patterns differ in normal and cancer cells, and if so, why?
Regulation of the histone methyl-transferase MLL (Nightingale, Wiersma)
Histone methylation plays an important role in activating or silencing genes, depending on the specific histone residue that is modified. The MLL family of histone methyl-transferases plays an important role in development, and mis-regulation by MLL ‘fusion’ proteins is causal for a number of leukaemias. Our ongoing research focuses on how the extracellular environment, through marks in chromatin, regulates MLL activity, and how this is dysregulated in tumours.
Epigenetic marks through the cell cycle in embryonic stem cells (O’Neill, Goss)
The Carrier Chromatin ImmunoPrecipitation (CChIP) technique developed in our laboratory is being used to assay embryonic stem cells in different cell cycle phases, isolated by flow cytometry. The work will show how histone modifications across key genes change as cells grow and divide.