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• W2896772311 abstract "The goal of this study was to nominate possible enhancers (regulatory regions that enhance transcription) for genes that are associated with neurodegenerative diseases. We selected Amyloid Precursor Protein (APP), Progranulin (GRN), LRRK2, and C9orf72 as genes of interest because of their connections to Alzheimer's, Frontotemporal dementia (FTD), Parkinson's, and ALS/FTD, respectively. We nominated enhancers using bioinformatics tools, and tested top candidates with a luciferase assay. Specifically, enhancer regions were nominated based on presence in predicted topologically-associated domains, and the presence of chromatin marks associated with enhancers: H3K27Ac, H3K4Me1, and DNase Hypersensitivity in both the A549 cell line (where elements were tested) as well as fetal and adult brain tissue. We used a script developed in house to z-score datasets and quantitatively nominate regions with z-score peaks across multiple data types to generate a list of possible enhancer regions. Nominated regions were tested in a luciferase assay. Candidate enhancers included nine 500 base pair sequences in proximity to the GRN, APP, LRRK2, and C9orf72 genes. Negative control regions from nearby regions that did not display enhancer characteristics were also selected. Of the 36 elements that were successfully synthesized and cloned, 8 elements showed activity (defined as statistically significant signal above background, as well as at least 5-fold change in signal over background) in the luciferase assay in A549 cells, including 2 from APP, 4 from GRN, 0 from LRRK2, and 2 from C9orf72. These results justify further investigation of their possible role as enhancers using orthogonal assay types, such as ablation of the elements in situ using CRISPR/Cas9 and subsequent measurement of transcript levels of the gene of interest using qPCR, experiments that are currently in process. A better understanding of the regulation of the APP, GRN, LRRK2, and C9orf72 will provide new insights into their roles in disease. Furthermore, mechanistic insights gained from study of the regulation of these genes may reveal new pathways of potential therapeutic relevance." @default.
• W2896772311 created "2018-10-26" @default.
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• W2896772311 date "2018-07-01" @default.
• W2896772311 modified "2023-10-16" @default.
• W2896772311 title "P1‐171: MAPPING ENHANCER REGIONS FOR GENES ASSOCIATED WITH NEURODEGENERATIVE DISEASES" @default.
• W2896772311 doi "https://doi.org/10.1016/j.jalz.2018.06.175" @default.
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