Institute of Biological and Biomedical Sciences
Epigenetics and Developmental Biology
The focus of research in this division is on the genetic and epigenetic mechanisms of development and differentiation and the genetic basis of disease. Xenopus and chicken are used as model organisms, aimed at establishing the role of genes that are important in developmental processes. Developmental research themes include the control of Gata2 and its role in blood formation, promoter structure in gene activation, retinoid signalling in neural differentiation, the control of neuronal identity and axon guidance in the early brain, and the genetic programming of muscle differentiation (Guille, Dietrich, Schubert).
Epigenetic themes encompass chromatin modifying enzymes and their role in gene regulation and the roles of histone modifications and primary sequence variants in cell differentiation, development and disease states (Thorne, An) There is a strong interest in Molecular and Genetic Medicine, e.g. neuromuscular disease and neuronal function in disease, with particular emphasis on the molecular pathology of Duchenne muscular dystrophy and the role of dystrophin and related proteins (Gorecki).
Our current research
Analysing gene function in development
The formation of a specific differentiated cell type during development is determined by the interplay of genes in a regulatory network. Understanding these networks is important because a defect in a key gene within the network will often lead to disease. This research uses the frog, Xenopus, as a model system, taking advantage of close links with the European Xenopus Resource Centre. The group is looking at transcription factors regulating the formation of blood cells or neurones and one area of particular interest is the interaction of transcription factors that bind regions of DNA that have an unusual structure.
Formation of the early axon scaffold
The adult vertebrate brain is a highly complex organ, containing billions of neurones each connected in a precise pattern by axonal outgrowths. The basic organisation of the brain is highly conserved in vertebrates and arises during early development when the first neurones establish a simple scaffold of axon tracts. The group is investigating the molecular programme, mainly in the chick embryo, that underlies the development of early neurons and how they interact with surrounding tissues.
Vascularisation and axon outgrowth in the developing brain
The intricate pattern of blood vessels in the brain depends on interactions between neural cells and blood vessel precursor cells. Using both Xenopus and chick embryos, the group is investigating the signals that pass between these two types of cell to determine the timing and pattern of blood vessel formation. Apart from its physiological importance in providing a blood supply for the brain, defects in vascularisation cause pathological conditions, whilst the formation of additional blood vessels by angiogenesis plays a significant role in tumour growth.
Epigenetics and the role of histone variants
Within the eukaryotic nucleus DNA is organized into nucleosomes and higher orders of folding by the histone proteins. However, the activity of the packaged genes can be regulated by biochemical modification of specific residues found mainly on the histone tails. Histone modifications can be related to gene expression across the genome that are conserved in a wide range of systems from vertebrate embryos to the intestinal cells of marine wood-boring invertebrates. Additionally, replacement of canonical histones by variants allows analysis of unique functions by ‘knock-down’ in Xenopus embryos.
The mitochondrial mutation research team is currently investigating mitochondrial genetic variations linked to breast to brain metastasis. Utilising the next generation sequencing (NGS), a 3D protein structural modelling and a range of biochemistry, cellular & molecular assays, we aim to identify functional mitochondrial DNA (mtDNA) variations as effective biomarkers to predict a high risk of brain metastasis. Another goal of the team is to identify mtDNA variations associated with varied treatment response (part of a large programme on personalised medicine led by Prof. Geoff Pilkington’s Neuro-oncology Research Group within IBBS).
The molecular medicine team is investigating pathomechanisms of Duchenne muscular dystrophy. We are interested in abnormalities downstream from the missing dystrophin, which occur in skeletal muscles but also in non-muscle tissues affected by this disease (e.g. brain). In particular, we study the role of purinergic (ATP) receptors trying to establish whether up-regulated expression and function of specific purinoceptors could be a novel therapeutic target in this incurable disease.
European Xenopus Resource Centre
The European Xenopus Resource Centre (EXRC) is funded by the Wellcome Trust, BBSRC and NC3Rs to support researchers using Xenopus models. Researchers are encouraged to deposit Xenopus transgenic and mutant lines, Xenopus in situ hybridization probes, Xenopus specific antibodies and Xenopus expression clones with the Centre. EXRC staff perform quality assurance testing on these reagents and then make them available to researchers at a small cost. EXRC can also supply wild-type Xenopus, embryos, oocytes and Xenopus tropicalis fosmids.