150 Oral - Chromatin
Saturday April 09, 9:30 AM - 9:45 AM

Authors:
Eve Lowenstein ¹; Andrew Adey ¹; Doris Kretzschmar ²

Affiliations:
1) Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR; 2) Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, OR

Keywords:
a. chromatin structure; a. neural degeneration

Frontotemporal dementia (FTD) is a neurodegenerative disease associated with mutations in the microtubule binding protein Tau. The clinical presentation of FTD is heterogeneous with patients exhibiting parkinsonism, dementia, atrophy in the temporal lobes, and personality changes. Current treatments can mitigate aspects of the behavioral changes associated with FTD, however, no therapies are available to slow the progression. Since patient sample procurement is restricted to post-mortem tissue, our understanding of the progression and underlying pathogenic mechanisms of this disease is limited. Recent work in model systems and post-mortem tissue has shown that expression of FTD-associated mutant Tau may lead to epigenetic modifications that alter gene expression. In our lab, we model FTD using Drosophila, which allows us to conduct longitudinal studies to observe FTD progression throughout the adult lifespan. The adult Drosophila expressing FTD-associated mutant human Tau (hTau) have age-dependent neurodegenerative vacuoles, axonal changes, locomotion defects and impaired memory while flies expressing normal hTau did not. This confirms that our models show pathogenic phenotypes associated with Tauopathies and it provides the basis to now use these models to identify molecular mechanisms of pathogenicity. We also found changes in a chromatin associated protein, Heterochromatin Protein 1 and hypothesized that FTD mutant Tau could alter chromatin accessibility. We used Single-cell Combinatorial Indexed Assay-for-Transposase-Accessible Chromatin using sequencing (sci-ATAC-seq) to assess how human Tau FTD mutations alter chromatin accessibility in the young and aged adult Drosophila brain for three clinically distinct Tau mutations (K369I, P301L, V337M). We generated >90,000 single-cell chromatin accessibility profiles from whole adult heads. Comparing our wildtype hTau insertion line to the FTD mutants revealed differentially accessible regions in both neuronal and glial cell populations. This work will further our understanding of chromatin structure in hTau knock-in models at single-cell resolution and provide insight into cell-type specific variation.