Exploring the role of epigenetic mechanisms in the manifestation of Huntington's disease

Huntington's disease (HD) is a neurodegenerative disease caused by an expansion of typically 40 or more repeats of the DNA code "CAG" in the Huntingtin (HTT) gene. The disease is characterised by movement disturbances, cognitive impairments, and psychiatric symptoms and there is currently no disease-modifying treatment. The size of the CAG repeat is closely associated with the age of symptom onset, with individuals with high numbers of repeats developing the disease at a young age. However, there is variation in the age of symptom onset between individuals with the same CAG repeat length. It is known that the expression of genes relies not only on a person's specific DNA code (their genome) but can also be altered by an extra level of information called the "epigenome". Epigenetic processes are chemical tags added to the DNA or histone proteins that turn genes on and off and can be influenced by external factors. We have recently shown robust alterations in two epigenetic marks (DNA methylation (DNAm) and H3K27ac) in Alzheimer's disease (AD). We have also seen DNAm differences in a pilot study of HD brain. We hypothesise that epigenetic mechanisms contribute to the manifestation of HD and plan to use state-of-the art genomic technology and computational approaches to undertake the most comprehensive study of epigenetic mechanisms in HD brain to date. We have the following complimentary work-packages:

WP1: (EPI)GENETIC CHARACTERISATION OF HTT USING LONG-READ SEQUENCING
We will use cutting-edge long-read sequencing technology to measure the length of the CAG repeat and extent of DNAm across that region of the HTT gene. This will allow us to determine exactly where DNAm is seen in the CAG repeat in HD brain samples. We plan to study two brain regions: the striatum and prefrontal cortex, which are affected at different stages of the disease. It is reported that the CAG repeat length can increase in some cells with age, which is termed somatic mosaicism. One advantage...