The potential for using embryonic cells, induced pluripotent stem cells and somatic stem cells in regenerative medicine approaches is the subject of intense research. Researchers are investigating the use of stem cells to treat a wide range of conditions from Parkinson’s disease to diabetes, and examples of ongoing clinical trials include the use of neural stem cells to treat stroke patients, and the use of mesenchymal stem cells to treat heart disease.
Within the field of cancer biology, cancer stem cells often share essential features with related tissue-restricted stem/progenitor cells. For example, it is thought that neural stem/progenitor cells within the sub-ventricular zone of the brain are a likely origin for glioblastoma multiforme. Neural stem/progenitor cells are fundamental for brain development and for adult learning, memory and repair following injury. Recent evidence supports a key role for cancer stem cells in glioblastoma multiforme development, and these cancer stem cells share essential features with adult neural stem cells.
In order to fully realise the therapeutic potential of stem cells, and to understand how somatic stem cells are related to cancer stem cells, is important to understand the genes and signalling pathways that underpin the properties of self renewal, (pluri)potency and differentiation. My lab is interested in the roles that chromatin and epigenetics play in the regulation of gene expression in embryonic stem (ES) cells and during neuronal differentiation. Studies have revealed that chromatin structure in ES cells is different to that of somatic cells. The chromatin appears to be less condensed, and is permissive for low level transcription of many, if not all, somatic genes. Key developmental genes also have a distinct “bivalent” epigenetic signature in ES cells, which is thought to regulate their expression during various differentiation pathways.
We have optimised an in vitro neuronal differentiation system and are using chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) to investigate how the distribution of epigenetic marks changes during pluripotent stem cell differentiation. We are studying how transcription factors and chromatin modifiers manipulate the histone code at enhancers and promoters to regulate gene expression during neuronal differentiation. We are also collaborating with Prof. Anthony Chalmers to study epigenetic profiles in glioblastoma stem cells, and are investigating how these differ in differentiated glioblastoma cells and normal neural stem cells.
Much of our work has focused on a family of small chromatin-binding proteins called the Hmgn proteins, which influence both chromatin structure and epigenetic marks. Hmgn2 is essential for early embryonic development, as Hmgn2 knockout embryos die early in development. Hmgn proteins are highly expressed in dividing neural stem/progenitor cells in the developing brain, and are also highly expressed in the subventricular zone (SVZ) and dentate gyrus of the hippocampus in adult brain. These are sites of continuing adult neurogenesis, and the dentate gyrus is particularly important for adult learning and memory. Our recent results have shown that knockdown of Hmgn proteins affects the expression of many key genes in pluripotent stem cells, and also disregulates several genes in differentiating neurons that control neurogenesis and neural stem cell identity. We are currently investigating the epigenetic mechanisms that are regulated by Hmgn proteins.
Interested in joining us?
We are always keen to talk to students and researchers interested in joining our group. As outlined above, we use genome-wide and gene-specific approaches in cultured cells, as well as in vitro biochemistry methods, to address our aims. Techniques include chromatin immunoprecipitation, next generation (high throughput) sequencing, real time PCR, immunfluorescence, tissue culture and FACS. There are also many opportunities for collaborative projects with other groups in Glasgow, particularly in the areas of cancer biology, stem cells, neuroscience and bioinformatics.