Epigenetic mechanisms during critical periods of development
Supervisor
A key aspect of nervous system development is the specification of homeostatic setpoints; to allow for appropriate network function and stability. We identified so-called ‘critical periods’ as defined developmental windows during which this occurs, and metabolic reactive oxygen species as instructive signals. Disturbances of these are thought responsible for neuro-developmental psychiatric conditions that commonly emerge during critical periods of human brain development.
We are investigating the mechanisms by which transient disturbances during the embryonic critical period leads to lasting changes in neuronal growth, excitability and synaptic properties, thus permanently changing network function and behaviour. Working with the powerful genetic experimental model, the fruit fly Drosophila melanogaster, we find that epigenetic modifications are linked to critical period manipulations. Now we can ask: how do metabolic signals cause changes in chromatin marks? And how are those maintained through later life to effect lasting change in cellular properties and function?
In this project you will use novel genetic tools for cell type-specific chromatin and transcriptomic profiling. You will use a combination of genetics, opto-genetics, functional imaging and electrophysiology to characterise how critical period-regulated changes in gene expression lead to changes in neuronal structure and function.
References
1. Oswald MCW, Brooks PS, Zwart MF, Mukherjee A, West RJH, Giachello, CNG, Morarach K, Baines RA, Sweeney ST and Landgraf M. (2018). Reactive Oxygen Species Regulate Activity-Dependent Neuronal Structural Plasticity. eLife, 7. http://doi.org/10.7554/eLife.39393
2. Giachello CNG, Fan YN, Landgraf M, Baines RA (2021). Nitric oxide mediates activity-dependent change to synaptic excitation during a critical period in Drosophila. Sci Rep. 2021 Oct 13;11(1):20286. doi: 10.1038/s41598-021-99868-8.
3. Aughey GN, Cheetham SW, Southall TD (2019). DamID as a versatile tool for understanding gene regulation. Development 146:dev173666. doi: 10.1242/dev.173666
Image: Epigenetic marks in muscle nuclei (yellow), showing nerves (magenta) and actin (cyan). Enlarged inset shows muscle nucleus and chromatin DamID analysis strategy.