EFRI CEE: Engineering and imaging 3D genome folding dynamics to control transcriptional misregulation in Alzheimer's disease

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This project seeks to discover new molecular understanding of the genetic defects in Alzheimer's disease (AD), a neurodegenerative disorder that progressively disrupts cognitive function in millions of Americans. The research team will use multi-disciplinary approaches and state-of-the-art methods to test the idea that single-base changes in genes associated with AD alter the three-dimensional (3D) packaging or folding of the genome, thereby disrupting gene activity and causing neuronal dysfunction. In parallel, they will build and test tools to re-fold pathologically tangled DNA into a configuration that will reverse some aspects of the malfunctioning genes in AD. The project will also have educational impact through development of innovative courses and training opportunities to attract and retain the highest level of next-generation talent, with a particular emphasis on under-represented minorities, for careers in the new field of genome engineering. In the long term, the research and training efforts have the potential to make positive contributions towards engineering better medicines for diseases such as AD. A critical unknown is how rare and common single nucleotide variants in noncoding regions of the genome govern the misregulation of gene expression that occurs in human disease. The goal of this project is to elucidate how the 3D genome and long-range gene regulation is disrupted in developing neurons by the genetic variants that cause AD. The project will focus on investigating the 3D epigenome as a new unexplored dimension in understanding and reversing the pathological transcriptional phenotypes that occur in sporadic and familial forms of AD. Cutting-edge molecular and imaging technologies will be used to query the structure and dynamics of genome folding at unprecedented resolution and scale during neural lineage commitment in healthy cells and in cells with AD mutations. The resulting outcomes will be used to build predictive models to explain how genomic miswiring is linked to pathological transcriptional disruption. Then the models will be tested by developing new engineering strategies for directing changes in genome topology on demand to reverse transcriptional defects. This work is broadly significant because it provides new quantitative models and genome engineering tools to reveal how modifications to the DNA sequence work through long-range, higher-order folding mechanisms to govern the gene expression profiles critical for proper neuron function. Addressing this knowledge gap will provide an essential foundation for the team's long-term goal to engineer the 3D genome to control neural cell fate in debilitating neurodevelopmental and neurodegenerative diseases.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.