007-23 – The role of SINE-VNTR-Alu retrotransposons in neurodegenerative diseases

SINE-VNTR-Alu (SVA) retrotransposons are genomic insertions which can create genetic variability within the population. SVA’s have been shown to act as regulatory sites for gene expression. We are investigating an SVA, named SVA_67, which is found in the MAPT locus. This locus is dense in coding DNA, and is characterised by an inversion approximately 970kb long, creating two different haplotypes: H1 is the human reference sequence; and H2 is the inversion of the H1 sequence. The presence of SVA_67 is associated with the H1 haplotype, while absence of this element is associated with the H2 haplotype. The MAPT gene and the MAPT locus are implicated in a number of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s Disease (PD), and Frontotemporal Dementia (FTD). In our study, we investigated KRAB-ZNF91 as a transcription factor that may bind to SVA_67, along with the co-factor KAP1, in order to characterise their potential role in transcriptional regulation at the MAPT locus. We used a cell model to investigate differences in gene expression at the MAPT locus when SVA_67 is present, and when SVA_67 is hemizygously knocked out. We applied challenges to these cell lines through overexpression of ZNF91 and knockdown of KAP1, measuring the changes these challenges elicited on local gene expression. We found differential effects of these challenges on gene expression where SVA_67 was present and where SVA_67 was knocked out, implicating SVA_67 as a regulatory domain for transcription factor binding in the MAPT locus. These experiments highlight SVA_67 as an important site for gene regulation in the MAPT locus, and as a potential biomarker for investigating neurodegenerative diseases, and their heritability.