UC San Diego

Microglia, the brain’s resident macrophage, display a diverse array of phenotypes in the adult brain. Alzheimer’s Disease (AD) is associated with a unique subtype of these cells which transmit excessive inflammatory signals resulting in both synapse and cell loss. To investigate the role of DNA methylation in driving these responses, I profiled genome-wide methylation levels with single-nucleotide resolution in human microglia following in vitro exposure to either lipopolysaccharide or amyloid-beta. I defined specific changes in the methylation landscape and established an important role for both 5-methylcytosine and 5-hydroxymethylcytosine in directing inflammatory and phagocytic processes in response to different stimuli, thus implicating differential methylation as a possible mechanism by which microglia convert to an AD-associated neurotoxic phenotype. Furthermore, I provide preliminary evidence that DNA methylation changes are integral to mounting an inflammatory response in vivo.