Transposable elements as hidden neuronal gene regulators in health and disease

In this thesis, we take several approaches to unravel the roles of transposable elements (TEs) and Krüppel-associated box (KRAB) domain zinc finger proteins (KZNFs) in gene regulation. By doing so, we aim to contribute to broadening the knowledge on the involvement of these mobile genetic elements and their co-evolved repressor proteins in health and disease. First, we provide insights into the gene-regulatory potential of TEs in different developing and adult brain regions, and assess if the enhancer activity of TEs is influenced by ageing and age-related neurodegenerative diseases. Next, we dive deeper into specific classes of TEs, the MER52 and SVA elements, and analyse the relationship with the KZNFs binding most abundantly to these elements: ZNF519 and ZNF91. Lastly, we focus on the involvement of structural variation within TEs in disease risk. We highlight the presence of structurally variable SVAs (SV-SVAs) in neurological disease-associated loci, and assess their association to disease-associated SNPs and differential gene expression. Thereby we reveal a novel layer of genetic variation in transposable elements that may contribute to identification of the structural variants that are the actual drivers of disease associations of GWAS loci.