Genomic Approaches to Dissect Innate Immunity in Neurodegeneration Christopher K. Glass UC San Diego, CA, USA Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. Although dysregulation of microglia activity is genetically linked to neurodegenerative and psychiatric diseases, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We recently characterized transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue, revealing that genes associated with risk alleles or exhibiting altered expression in neurodegenerative diseases are preferentially or highly expressed in human microglia in comparison to intact brain tissue. The transition of human and mouse microglia from the brain to a tissue culture environment results in rapid and extensive downregulation of genes, identifying sets of environmentally sensitive transcripts. These findings revealed an environment-dependent transcriptional network specifying the microglial gene expression program and will facilitate efforts to better understand the roles of microglia in human disease. Moving forward, we are applying a combination of genetic and genomic approaches to better understand mechanisms by which non-coding genetic variants associated with risk of neurodegenerative disease regulate microglia gene expression and phenotype.
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