Functional role of genetic variation in cell-specific pathogenesis of AD
Alexi Nott1,6, Johannes C.M. Schlachetzki1,6, Martina P. Pasillas1, Inge R. Holtman1, Zhengyu Ouyang1, Claudia Han1, Robert A. Rissman3,4, James B. Brewer3,5, Christopher K. Glass1,2
1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; 2Department of Medicine, University of California, San Diego, La Jolla, CA, USA; 3Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; 4Veterans Affairs San Diego Healthcare System, San Diego, La Jolla, CA, USA; 5Department of Radiology, University of California, San Diego, La Jolla, CA, USA;
6Authors contributed equally
Sporadic Alzheimer's disease (AD) has no clear genetic cause, however, ~20 risk alleles have been identified by GWAS. Most AD-risk alleles are within non-coding regions that are likely located in enhancer elements and many are near genes expressed in microglia. Enhancers are short regions of DNA that when bound by transcription factors enhance expression of nearby genes. Active enhancers can be identified as regions of open chromatin with distinct histone acetylation patterns, such as acetylation of histone H3 lysine 27 (H3K27ac). Alterations in enhancer landscapes are linked to changes in gene expression and can infer the identity of transcription factors that drive these changes. Human genetic variation is thought to affect enhancer selection and is likely a major determinate of cell-specific differences in gene expression between individuals. However, the epigenetic landscape has not been mapped in specific cell types of the human brain. We hypothesize that cell-specific enhancer atlases in AD will reveal regulatory functions of AD-risk alleles and identify signaling pathways and transcription factors associated with pathogenesis. Leveraging the brain bank of the Shiley-Marcos Alzheimer's Disease Research Center at UCSD, we have established a cell-specific nuclei isolation protocol for human brain samples, including myeloid and neuronal populations. Here, we present initial analysis of gene expression (RNA-seq), active enhancers (H3K27ac ChIP-seq), and regions of open chromatin (ATAC-seq) from cell-specific nuclei populations. Our findings will provide a better understanding of how human genetic variation influences the expression of genes associated with AD, potentially leading to innovative intervention targets.