Epigenetic factors that regulate hippocampal circuit assembly
Human intelligence and behaviour are functions of the neural networks that comprise the central nervous system. One of the key cognitive functions of the brain is the formation of memories, a task that is critically dependent on the hippocampal formation. Transcription factors (TFs) play key roles in directing neural circuit assembly in the hippocampus through their precise spatial, temporal, and cell type-specific control of gene expression. Moreover, epigenetic factors that act through DNA methylation, chromatin modifications and higher order chromatin remodelling, add further levels of complexity to the regulation of hippocampal development.
We have identified a TF complex that is important for the development of hippocampal neural circuitry. Loss-of-function mutations that affect the composition of this complex are associated with changes in the prevalence of specific post-translational chromatin modifications, e.g. H3K27me3, suggesting that the complex acts mainly through epigenetic mechanisms.
The purpose of this study is to investigate the genes regulated by this TF complex for associated changes in the prevalence of different histone marks and identify the chromatin modifying enzymes that are responsible. For example, H3K27 is methylated only by the SET methyltransferase EZH2, and demethylated by JMJD3 and UTX1. The student will investigate the expression of these enzymes and changes in prevalence of specific histone marks in the developing hippocampus using immunohistochemistry and confocal imaging, chromatin immunoprecipitation and high throughput sequencing.
As epigenetic factors are environmentally responsive and can be pharmacologically manipulated, this work may identify novel therapeutic targets to improve cognition and memory. For example, future experiments will investigate the impact of specific inhibitors of EZH2 (DZNep, MC1948)2 and JMJD3/UTX (GSKJ4)3 on hippocampal-dependent morphology, electrophysiology and neurobehaviour. The student will also learn to use bioinformatic tools to model dynamic changes in chromatin and gene expression throughout hippocampal development.
When applying please select ’Neuroscience PhD’ within the Faculty of Health Sciences.
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