Integrative epigenomic analyses of repetitive elements in neurodegenerative diseases

Abstract

Neurodegenerative diseases are complex in nature, often involving various cell types, dysregulated cellular pathways and chronic inflammation. In this report, I propose studying epigenetic changes of repetitive elements in neurodegenerative diseases using three mouse models. The first part probes longitudinal cis-regulatory changes in an Alzheimer’s Disease (AD) mouse model. AD is the most common form of dementia where molecular changes are thought to occur long before the onset of symptoms. Using H3K27ac ChIP-seq, I profile changes in regulatory elements from different mouse ages. Next, we examine the origins, characteristics and fate of cytoplasmic DNA (cytoDNA) using a DNA repair inhibition model. CytoDNA has been observed in a range of diseases, including neurodegeneration. Our work demonstrates that cytoDNA sequences are enriched with nuclear repeats which are actively exported to the cytoplasm upon DNA damage, thus contributing to inflammation. Lastly, we probe the link between retrotransposons and the expression of immune-related genes in oligodendrocyte precursor cells (OPCs), a key cell type in the autoimmune disease multiple sclerosis (MS). We utilise published datasets from interferon-gamma treated OPCs and identify potential retrotransposon candidates, including members of the RMER17 repeat subfamilies. We then generate RMER17 knockouts in an OPC cell line and show that immune upregulation is impaired. Taken together, these studies use epigenetic methods to profile changes in the non-coding genome and their roles in disease progression.

Date of Award	2023
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Danny Chi Yeu LEUNG (Supervisor)