Faculty Investigator Nick Cochran, PhD, and team members Rebecca Hauser, PhD, Sam Bartley, and Brianne Rogers helping to identify regulatory elements of MAPT results.
expression of MAPT in neurons compared to precursor cells and other cell types. Understanding how MAPT is regulated may point to new strategies to achieve tau reduction, which could be therapeutically beneficial. Developing drugs to stop the regulatory element’s ability to turn on genes that drive Alzheimer’s disease pathology could prevent the onset or slow the progression of the disease. While the lab is currently focused on fully investigating their MAPT dataset, they do plan to look at the regulation of other neurodegen- erative disease genes in the future, including SNCA , which codes for alpha-synuclein (important in Parkinson’s dis- ease) and APP , which is the precursor gene for the other key neuropathology in Alzheimer’s, beta-amyloid. ■
Using genomic approaches and the neural cell culture models, the team identified several regulatory elements of MAPT , some of which are proximal to its promoter and some that are over 500,000 bases away 1 . Chromatin capture and single-nucleus RNA- and ATAC-seq were used to identify regions within the MAPT locus and nominate regions correlated with MAPT expression. A luciferase reporter assay and CRISPR inhibition of the regulatory regions helped confirm their function. Previous groups identified an H2 inversion on chromo- some 17 that influences Parkinson’s disease, progressive supranuclear palsy (PSP), and Alzheimer’s disease. Using their ever-growing dataset, researchers in the Cochran lab found that in neurons, there is a regulatory region outside of the inversion that strongly influences MAPT expression. Based on their data, the lab believes that the regulatory elements could be neuron-specific and explain the high
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