All ETDs from UAB

Advisory Committee Chair

Richard M Myers

Advisory Committee Members

Sara J Cooper

Gregory M Cooper

Jeremy J Day

Anita B Hjelmeland

Erik D Roberson

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease, currently affecting more than six million Americans with limited treatment options. Identifying genetics contributors to neurodegenerative diseases has contributed critical insights into potential disease mechanisms. The majority of disease-associated genetic variants are located in non-coding regions, likely in regulatory elements, and affect the expression of target genes whose function contributes to neurodegeneration. Here, I performed a case-control study utilizing nuclei from dorsolateral prefrontal cortex postmortem tissue to correlate chromatin accessibility with gene expression and nominate 40,831 AD-specific candidate cis-regulatory elements. Additionally, work in this dissertation nominates ZEB1 and MAFB as candidate AD-specific trans-regulators in neurons and microglia, respectively. Tau abnormalities track closely with disease progression and are found in a spectrum of neurodegenerative diseases, termed tauopathies. Reduction, even partial, of tau has shown robust therapeutic benefits in AD mouse models. Given the relevance of tau to neurodegeneration pathogenesis, identification of elements regulating its expression is critical to understanding disease risk and pathogenesis. Using orthogonal genomics approaches, I nominated candidate cis-regulators of MAPT, which encodes tau. My work here identified both proximal and distal regulatory elements, and I confirmed function for 5 regions, including three regions centromeric to MAPT beyond the H1/H2 iv inversion breakpoint. Together, these findings represent the most comprehensive evaluation to date of cis-regulatory elements important for MAPT expression and provide compelling evidence for pursuing detailed knowledge of CREs for genes of interest to better understand disease risk.

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