Chromatin Structure and Function

 

The genetic information present in our DNA is stored in such a way that only the information required in specific tissues is accessible. Regulating what is accessible is regulated in part by energy consuming molecular motors that regulate the packaging of DNA. Some of these motors are found to be altered frequently in cancer cells. We study how these motors function and how alterations to them cause cancer.cryoempicture11

Regulating when genes are expressed is achieved in part by regulating what parts of the genome are accessible (Fennessy and Owen-Hughes, 2016; Wiechens et al., 2016; Hammond et al., 2016). A group of ATP-dependent motor proteins specialised to act in regulating accessibility provide one means of achieving this (Narlikar et al., 2013).

 We study these enzymes through collaboration and the application of new approaches especially genomics, imaging, structural biology and proteomics. It’s often the case that by working together with colleagues we can achieve more than we would in isolation.

 Looking forward we will focus our research on understanding how human chromatin remodelling enzymes act as tissue specific tumour suppressors. This new direction has arisen as a result of tumour genome sequencing which has revealed that subunits of human SWI/SNF related chromatin remodelling complexes are mutated at a frequency of 20% across all cancers (Kadoch and Crabtree, 2015). Even more mystifying, specific subunits are mutated in tumours of different tissues. To understand how this complex is altered following subunit loss in cancer we are engineering cell lines to study how subunit loss affects function in different cell types. Changes in the protein composition and genome wide distribution of the complexes will be characterised using the excellent in house facilities. In parallel we will collaborate with clinicians to identify changes that relate to tumour progression in patient material. We will also build the complex and its submodules from recombinant expressed proteins to study its biochemical properties and structure using techniques such as single particle cryo-electron microscopy. We will also assess the potential for chemical inhibition of the complex together with the Drug Discovery Unit in Dundee.

 In combination, the application of these approaches will describe how the action of these complexes is subverted in cancer. Ultimately this will improve detection and treatment of cancers that are driven by alterations to this complex.