Cell-type-specific epigenetic regulation of gene expression in Motor Neuron Disease MRC GW4 BioMed DTP PhD studentship 2025/26

Summary

This project aims to uncover new molecular insights into Motor Neuron Disease (MND) using advanced molecular technologies. It involves studying human post-mortem brain tissue and cells derived from patient

stem cells to examine gene regulation in different brain cell types. Specifically, the focus will be on different cells from patients with and without a large expansion in the C9ORF72 gene, the most common genetic cause of MND. Recent research indicates that C9ORF72 is modified in patient neurons and linked to patient survival. This project could lead to the discovery of new treatment targets for this incurable disease

Description

Motor Neuron Disease (MND) is a fatal incurable neurodegenerative condition characterised by loss of motor neurons(MN) which leads to progressive muscle paralysis with average survival 2–5 years after diagnosis. A repeat expansion in the C9ORF72 gene (C9RE) is MND’s most common genetic cause. Healthy individuals usually display around 2-3 repeats whereas >1000 repeats are commonly reported in MND patients. Downstream molecular consequences of this repeat expansion include lower C9ORF72 gene expression, and the formation of toxic nuclear RNA foci and protein aggregates, together contributing to motor neuron dysfunction and cell death.

Epigenetic processes mediate the reversible regulation of gene and orchestrate a diverse range of important neurobiological processes in the brain and CNS. DNA methylation is the most stable epigenetic modification and has been strongly implicated in the aetiology and progression of MND neuropathology. In particular, DNA methylation is altered at C9RE and is associated with both repeat length and disease progression. Importantly, increased DNA methylation at C9RE is associated with, later age at death and decreased disease duration. It

has also been correlated with transcriptional silencing of the C9ORF72 gene and decreased accumulation of toxic RNA foci suggesting that this DNA modification may have protective effects in repeat carriers and could be modifiable. 

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