The aim of my research is to understand how epigenetic regulators control gene expression during early brain development. In particular I am interested in how histone-modifying enzymes control the balance between self-renewal and differentiation to ensure appropriate brain growth. Understanding this balance is key to interpreting the molecular perturbations observed in a broad-range of neurodevelopmental disorders (NDDs).
Building a brain, the most compositionally and functionally complex human organ, requires the tightly coordinated expansion, specialization and migration of neural cell types. Transcription factors govern this process, however the spatial and temporal fidelity which is essential for brain function relies heavily on epigenetic modifiers. By altering the chemical and structural properties of chromatin, epigenetic systems ensure the proportionate transcriptional response to developmental cues. Accordingly, causal mutations in epigenetic regulators are prominent in both congenital and acquired brain disorders. Often the phenotypes and underlying genetic lesions of NDDs are known, yet the precise molecular aetiology is not. This is due to our limited understanding of how epigenetic systems drive gene expression programmes during normal brain development.
We combine cutting edge molecular techniques in combination with mouse and cell based model systems to understand the role played by epigenetic modifiers during brain development, and how their mutation contributes to disease.
- How are epigenetic modifiers targeted to chromatin in the developing brain?
- How do neural-specific protein components adapt the functionality of epigenetic modifiers?
- What is the relative contribution of histone modification activity for gene regulation in the neural lineage?
- Why do mutations in functionally opposing epigenetic regulators lead to equivalent disordered brain phenotypes?