Professor Tom Owen-Hughes
Gene Regulation and Expression, School of Life Sciences
+44 (0)1382 385796
Wellcome Trust Biocentre
Chromatin Structure and function.
The genomes of eukaryotes associate with histone proteins to form chromatin. Chromatin is the substrate for all genetic processes and as a result of fundamental importance to a diverse range of biological processes including development and disease. Indeed chromatin is currently of significant interest both in the development of biomarkers for diseases and as a source of new therapeutic targets. Eukaryotes use a range of strategies to alter chromatin structure. These include the use of histone modifications, histone chaperones and ATP dependent remodelling enzymes. We are generally interested in how these different strategies are coordinated to ensure appropriate gene regulation.
See Figure 1 below - Organisation of transcription and chromatin proteins with respect to the Transcriptional start site (TSS). Nucleosomes,histone modifications, histone chaperones exhibit distinct distributions with respect to transcribed genes. Adapted from (Owen-Hughes and Gkikopoulos 2012).
The application of rapidly developing genomic approaches to study gene regulation has revealed a common architecture shared by large numbers of transcribed genes. This consists of a nucleosome depleted region just upstream of the transcriptional start site, and an array of well positioned nucleosomes extending into the coding region (Figure 1). We have found that a combination of the Isw1 and Chd1 chromatin remodelling enzymes play a major role in maintaining this organization in yeast (Figure 2).
See Figure 2 below – ATP dependent chromatin remodelling enzymes contribute to genome wide chromatin organisation. High throughput sequencing can be used to map the positions of nucleosomes over all genes (green line). The organisation of nucleosomes over coding regions is lost in strains lacking the Isw1 and Chd1 enzymes (red line). Adapted from (Gkikopoulos et al 2011)
These observations raise many questions. For example, how is the action of these enzymes coupled to transcription? How is the chromatin of non transcribed regions organized in higher eukaryotes? Projects aimed at addressing these issues are ongoing.
We are also interested to learn at a molecular level how chromatin remodelling enzymes and histone chaperones engage with chromatin. For example we are using combined structural approaches to model the overall organization of the Chd1 protein and its interaction with nucleosomes. These include X-ray crystallography, which we used to solve the structure of the C-terminal domain of the Chd1 protein (Figure 3).
See Figure 3 below – The crystal structure of the C-terminal DNA binding domain of Chd1. The structure revealed the presence of SANT and SLIDE domains. We are currently investigating the role of these domains in nucleosome positioning and the configuration of full length Chd1 protein. Adapted from (Ryan et al 2011)
We are particularly interested in using Electron Paramagnetic Resonance (EPR) to dock domains of known structure with respect to each other. An example illustrating how we have used this to study the conformation of chromatin when associated with histone chaperone proteins is shown in Figure 4.
See Figure 4 below - Distance measurements obtained by EPR. Distance measurements were obtained from histones in complex with histone chaperones showing that they retain a tetrameric organisation (Bowman at all 2010, Bowman et al 2011)
PhD Student Seraina Blümli and colleagues from the Owen-Hughes lab show the ARID1A subunit of the BAF chromatin remodelling complex organised nucleosomes flanking pluripotency transcription factors and association of the coactivator EP300.
A University of Dundee researcher has been awarded £1.6 million in funding from UK Research and Innovation (UKRI) to develop machine learning tools for the life sciences.
Scientists at the University of Dundee and Boehringer Ingelheim have made an important first stride toward drugging undruggable cancer targets.
Chromatin structure and gene regulation
|Personal Fellowships / Wellcome Trust Senior Research Fellowship||2012|
|Fellows of the Royal Society of Edinburgh||2009|
|Personal Fellowships / Wellcome Trust Senior Research Fellowship||2007|
|Members of the European Molecular Biology Organisation||2007|
|National Sciences Prizes awarded since 1990 / The Colworth Medal of the British Biochemical Society||2002|
|International Science Prizes awarded since 1990 / EMBO Young Investigator||2000|