Potential Supervisors within this theme
Dr Constance Alabert
During lineage propagation, cells must duplicate their genetic and epigenetic information to maintain cell identity. However, the mechanisms underlying the maintenance of epigenetic information in dividing cells remain largely unknown. In S phase, progression of DNA replication forks provokes a genome-wide disruption of the epigenetic information. While nucleosomes are rapidly reassembled on newly replicated DNA, full restoration of epigenetic information is not completed until after mitosis. Our aim is to dissect the mechanisms that restore epigenetic information on newly replicated DNA. To this end we take advantage of the Nascent Chromatin Capture (NCC), a novel technology that allows the analysis of proteins associated with newly replicated DNA. We aim to identify and functionally characterize key players in the restoration of the epigenetic information in cycling cells and at specific loci. We aim to further investigate the pathological role of the newly identified chromatin factors, which are deregulated in human diseases as cancer. Altogether, these integrated approaches should provide new insights into the molecular mechanisms that coordinate genome and epigenome maintenance across cell generations.
Prof Julian Blow
The aim of our work is to understand at a molecular level the way that chromosome replication is regulated, and to apply this knowledge to improving the diagnosis and treatment of cancer. We use a number of two main model systems to study cell cycle control of DNA replication. Cell-free extracts of Xenopus eggs, which support all the nuclear events of the early embryonic cell cycle, provide a powerful system for studying DNA replication control at a biochemical level. We also use human tissue culture cells which have important advantages for studying DNA replication using cell biological and molecular genetic approaches. Current research projects are addressing: a) how the licensing system is regulated at different stages of the cell division cycle; b) how the Cdc7 and cyclin-dependent kinases trigger the initiation of DNA replication; c) how replication origins are physically organised on chromosomal DNA; and d) the potential of small molecule inhibitors of replication licensing to provide a novel anti-cancer treatment.
Prof Kim Dale
My lab looks at the molecular interactions and crosstalk between various signalling pathways that cells use to communicate to build tissues and organs during establishment of the vertebrate body axis. We focus on progenitor cell fate choice and segmentation as two key aspects of body plan formation. We have identified Notch as a key player in many of these processes and are focussing on the mechanism by which fine tuning the strength and duration of this pathway impacts on its function in various developmental contexts, using both in vivo and in vitro model systems. Since aberrant Notch signalling also underlies many diseases, including a variety of cancers, our findings will also be used to explore novel ways to modulate Notch function in cancer cell lines.
Dr Greg Findlay
Embryonic Stem Cells (ESCs) are pluripotent, which means they have the ability to differentiate into all specialized cell types found in the body, including brain, heart, lung, liver and pancreas. This has driven a huge research effort to develop strategies to exploit these cells for tissue replacement therapies in patients with a variety of diseases. Despite this interest in ESC biology, the signaling networks which control pluripotency and differentiation have not been extensively explored. In our lab, we seek to bridge this gap, as we believe that understanding how protein kinase signaling defines ESC identity will be essential to effectively apply pluripotent cells in regenerative medicine.
Dr Edgar Huitema
Our lab aims to understand the mechanisms by which P. capsici achieves virulence on and ravages multiple crops. Our research is guided by the observation that secreted molecules (effectors) from Phytophthora, play pivotal roles in disease establishment and epidemics. Genome sequences for an increasing number of distinct Phytophthora species now allows us to define the Phytophthora repertoires required for infection and host range. We are interested in the functional roles of effectors in epidemics and the factors that control their expression. With the new understanding about the role of effector proteins during disease and the availability of P. capsici genome sequences, we aim to study and perturb the pathways that control effector gene expression, delivery and their activities. Knowledge gleaned from this dynamic parasite will help us disable pathogenesis and control disease.The development of novel control methods that limits epidemics will help reduce P. capsici incited economic losses and improve disease management strategies of other oomycetes.
Prof Hari Hundal
The research programme in the Hundal lab is aimed at defining the intracellular signalling processes that regulate uptake, storage and metabolism of nutrients (e.g. glucose, fatty acids and amino acids) with particular focus on how cells sense nutrient availability and how nutrient over-load can induce metabolic disorders such as insulin resistance and diabetes. More recently, the Hundal lab has also opened up a new and exciting area of study that principally aims to develop our understanding of the action of a class of compounds, termed cannabinoids, in peripheral tissues such as skeletal muscle.
Dr Jens Jansuchke
How do cells become different from each other? One way to achieve this fundamental process is through asymmetric division, when a cell divides resulting in two cells of different fate. For instance, asymmetric divisions of stem cells occur in the developing nervous system of many different species including fruit flies and humans. Intriguingly, disrupting the correct specification of cell types by interfering with asymmetric stem cell divisions can trigger tumor-like growth. How then are different cell fates established through asymmetric division and how does this prevent uncontrolled tumor-like growth? Our research will use the powerful genetics of Drosophila, coupled with state of the art live cell microscopy and chemical genetics approaches to uncover the molecular mechanism that normally regulate asymmetric cell division of stem cells in the developing nervous system of the fly. There will also be a particular focus on exploring the role and regulation of kinases and protein phosphorylation in the context of cell polarity establishment and cell fate generation.
Prof Karim Labib
Chromosome replication is one of the most complex and fascinating of all cellular processes in eukaryotes, with mechanisms and regulation that are still understood poorly in all species. Many of the proteins involved in chromosome replication associate with each other to form a multi-protein assembly known as the replisome, which physically connects the essential DNA helicase that unwinds the parental duplex, to the DNA polymerases and other factors. My group is focussed on defining the nature of eukaryotic replisome, understanding its mechanisms of action, and studying its regulation by post-translational modifications. Most of the proteins that we study have a single orthologue from humans to yeast, reflecting the very high degree of conservation of the eukaryotic replisome, and indicating the value of using simple experimental systems. Our work exploits the unique advantages of budding yeast for studies of chromosome replication, combining state of the art biochemical and genetic techniques, but we are also extending our work into mammalian systems where appropriate.
Prof Angus Lamond
We are studying gene expression, RNA processing and disease mechanisms in human cells and model organisms. Our goal is to characterise structure/function relationships within the cell and to study protein dynamics at a systems level. We do this using a combination of quantitative techniques, including mass-spectrometry-based proteomics, cell and molecular biology, fluorescence microscopy and computational approaches for big data analytics and interactive data exploration. The use of high throughput proteomics technologies provides a system-wide approach allowing us to measure cellular responses for a large number of proteins in parallel. An integral part of this work is the development of new software tools for the management analysis and visualisation of complex proteomics data sets (see http://www.peptracker.com/).
Dr David Murray
We are interested in the regulation of cellular processes which are responsible for forming structures of the cell. In particular, we are interested in the structures formed by polarized trafficking, such as cilia and tight junctions. By harnessing a wide array of biochemical, biophysical, and cell biological methods, we are tackling mechanisms with direct disease relevance with a unique approach.
Prof Inke Nathke
The aim of work in my laboratory is to determine the molecular mechanisms that govern the role of the APC protein in cell migration, adhesion and division and includes investigating the relationship between different protein interactions of APC in vivo. The experimental approaches we use include whole tissue, cultured cells, in vitro assays combined with cellular and molecular biology techniques as well as high-resolution fluorescence microscopy.
Prof Tom Owen Hughes
One of the unanticipated outcomes of population based genome sequencing is the high frequency of mutations to apparently ubiquitous transcriptional and chromatin regulators in tissue specific cancers. This is the case for SWI/SNF – related chromatin remodelling complexes. Subunits of these complexes are mutated in about 20% of all tumours and at higher frequencies in cancers of specific tissues. To understand how these genes function we have engineered stem cell lines in which specific subunits of these enzymes can be degraded rapidly and specifically. This reveals a subset of genes directly affected by alterations to the composition of the complex driver slower and more widespread reprogramming of the cells.Human stem cells will be engineered to allow conditional removal of the main drivers for clear cell renal cancer (ccRCC), the SWI/SNF complex subunit PBRM1 and the E3 ligase VHL. Genes identified to be misregulated following loss of these tumour suppressors in an organoid model of human kidney represent potential therapeutic targets for what is the 9th most common cancer in the UK. Candidates will be selected on the ability to reverse the signatures of ccRCC tested.
Dr. Kasper Rasmussen
The aim of our work is to dissect the mechanisms by which the proteins regulating the DNA methylation landscape affects chromatin structure and gene expression patterns in hematopoietic cells. To do this, we utilize CRISPR genome editing in embryonic stem cells, mouse and human hematopoietic cell lines and complex mouse models of leukemia and combine these with the application of new biochemical, genomics and proteomics techniques. The biological insights obtained may provide the basis for developing targeted therapies for blood cancers with mutations in the DNA methylation machinery.
Prof Pauline Schaap
Most protozoa survive environmental stress by encapsulating to form a cyst or spore. Dictyostelid social amoebas survive stress by building fruiting structures with encapsulated spores and stalk cells. Both cell types mature in response to cAMP activation of PKA. We showed earlier that this process is evolutionary derived from encystation in solitary amoebas, which we found to also require cAMP acting on PKA. The encysting Dictyostelid Polysphondylium pallidum is uniquely suitable for both reverse and forward genetic approaches, which allowed us to identify several encystation genes that proved to be deeply conserved in protozoa. In current research we combine the power of genetics with proteomic approaches to identify all genes that control encystation in P.pallidum.
Dr Gabriele Schweikert
Epigenetic mechanisms may provide the living cell with a system to efficiently use the specific information required for each cells’ specific needs,” Gabriele explained. “Currently, we have only limited understanding of its architecture and working, however, with modern high-throughput technologies we can register epigenomic snapshots of current states of cells. The data is very complex, high-dimensional, redundant and dynamic. A truly interdisciplinary approach is required that combines expert knowledge of epigenomic mechanisms with machine learning technologies. The impact of understanding these epigenetic processes holds immense promise for medical applications. For instance, malfunctioning of the epigenetic machinery are increasingly recognised as important contributors to tumourigenesis (e.g. in leukaemia).
Prof Kate Storey
We wish to understand how neural cells arise and how their proliferation and differentiation are controlled. Our work focuses on the developing spinal cord and insights from these studies inform our investigation of these processes in embryonic stem cell derived neural tissue and in maturing spinal cord progenitors, which become adult neural stem cells. Our most recent research includes investigation of effects of metabolic and environmental stress on neural development. We use cell specific gain and loss of gene function approaches as well as genome-wide analyses and real-time imaging techniques. The overall aim of our work is to identify cell biological and gene regulatory mechanisms that direct neural differentiation, with a long-term goal to inform strategies for therapeutic treatment of neural injury and disease.
Prof Jason Swedlow
Our research is focussed on developing and using novel collections of multi-dimensional image databases for discovery of biological mechanism and dynamics. We have built and run the world’s largest public bioimage data collection—the Image Data Resource (IDR; [https://idr.openmicroscopy.org)--]https://idr.openmicroscopy.org)-- which contains millions of highly annotated image datasets from many independent studies. We have shown that we can use this collection to identify biomolecular interactions and complexes. Our future work will involve the development of a novel field of bioinformatics by exploring the links between molecular perturbations and phenotypes in the IDR.
Prof Tomo Tanaka
To maintain genetic integrity, eukaryotic cells must inherit a whole set of their chromosomes when they divide. Errors in this process would cause cell death and various human diseases such as congenital disorders and cancers. Our research aims to reveal fundamental mechanisms ensuring chromosome inheritance (segregation) during mitosis. We study this process in human and yeast cells using advanced microscopy, genomic/proteomic approaches, in vitro reconstitution and mathematical modelling/simulation.
Prof Kees Weijer
Cell movement is often guided by gradients of diffusible attractive and repulsive signalling molecules (chemotaxis). Important open questions are how do cells after detection of gradients of chemo-attractants/repellents translate this information in polarised organisation of the actin myosin cytoskeleton to result in directed movement up or down these signalling gradients?. A further key question is how chemotactic signalling and cell movement interact to create new tissues? We study these questions using a variety of multidisciplinary approaches in two model organisms, the genetically tractable social amoebae Dictyostelium discoideum and during gastrulation in the chick embryo.
Dr Ulrich Zachariae
We apply and develop simulation methods on a range of length and time scales, especially focusing on membrane proteins and ion channels. Membrane-bound proteins form a large part of the proteome and control many of the cell's fundamental functions. To investigate ion channels, we have developed CompEl, "computational electrophysiology", which allows the prediction of channel ion conductance and selectivity based on electrochemical gradients. Of special interest to us are potassium channels, G-protein coupled receptor signal transduction, and antibiotic permeability across the membranes of bacteria.